WO2019028302A1 - Substituted indole compounds useful as inhibitors of tlr7/8/9 - Google Patents

Substituted indole compounds useful as inhibitors of tlr7/8/9 Download PDF

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Publication number
WO2019028302A1
WO2019028302A1 PCT/US2018/045082 US2018045082W WO2019028302A1 WO 2019028302 A1 WO2019028302 A1 WO 2019028302A1 US 2018045082 W US2018045082 W US 2018045082W WO 2019028302 A1 WO2019028302 A1 WO 2019028302A1
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Prior art keywords
indol
isopropyl
piperidin
dimethylpyridin
methyl
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PCT/US2018/045082
Other languages
French (fr)
Inventor
Alaric J. Dyckman
Dharmpal S. Dodd
Tasir Shamsul Haque
Brian K. Whiteley
John L. Gilmore
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Bristol-Myers Squibb Company
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Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to ES18756116T priority Critical patent/ES2909401T3/en
Priority to CN201880050864.0A priority patent/CN110997656B/en
Priority to US16/635,593 priority patent/US11447466B2/en
Priority to JP2020505835A priority patent/JP7104775B2/en
Priority to EP18756116.2A priority patent/EP3661926B1/en
Priority to KR1020207005967A priority patent/KR102651947B1/en
Publication of WO2019028302A1 publication Critical patent/WO2019028302A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention generally relates to substituted indole compounds useful as inhibitors of signaling through Toll-like receptor 7, 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof.
  • substituted indole compounds useful as inhibitors of signaling through Toll-like receptor 7, 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof.
  • substituted indole compounds compositions comprising such compounds, and methods of their use.
  • the invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to TLR modulation, such as inflammatory and autoimmune diseases, and methods of inhibiting the activity of TLRs in a mammal.
  • Toll/IL-1 receptor family members are important regulators of inflammation and host resistance.
  • the Toll-like receptor family recognizes molecular patterns derived from infectious organisms including bacteria, fungi, parasites, and viruses (reviewed in Kawai, T. et al, Nature Immunol. , 1 1 :373-384 (2010)).
  • Ligand binding to the receptor induces dimerization and recruitment of adaptor molecules to a conserved cytoplasmic motif in the receptor termed the Toll/IL-1 receptor (TIR) domain. With the exception of TLR3, all TLRs recruit the adaptor molecule MyD88.
  • the IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, J.E. et al, Nature Rev. Immunol , 10: 89-102 (2010)).
  • TLRs Toll-like receptors
  • TLR9 transmembrane innate immune receptors that participate in the first-line defense. As pattern recognition receptors, the TLRs protect against foreign molecules, activated by pathogen associated molecular patterns (PAMPs), or from damaged tissue, activated by danger associated molecular patterns (DAMPs).
  • PAMPs pathogen associated molecular patterns
  • DAMPs danger associated molecular patterns
  • TLR7-9 are among the set that are endosomally located and respond to single-stranded RNA (TLR7and TLR8) or unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs (TLR9).
  • TLR7/8/9 can initiate a variety of inflammatory responses (cytokine production, B cell activation and IgG production, Type I interferon response).
  • cytokine production cytokine production
  • B cell activation cytokine production
  • IgG production Type I interferon response
  • the present invention relates to a new class of substituted indole compounds found to be effective inhibitors of signaling through TLR7/8/9. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.
  • the present invention provides compounds of Formula (I) that are useful as inhibitors of signaling through Toll-like receptor 7, 8, or 9 and are useful for the treatment of proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • the present invention also provides a method for inhibition of Toll-like receptor 7, 8, or 9 comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or
  • the present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • the present invention provides a method for treating inflammatory and autoimmune diseases.
  • inflammatory and autoimmune diseases include, but are not limited to, Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, adult onset Still's disease, systemic onset juvenile idiopathic arthritis, multiple sclerosis.
  • the first aspect of the present invention provides at least one compound of
  • R2 is Ci-6 alkyl, C1-3 fluoroalkyl, Ci-6 hydroxyalkyl, C 1-3 aminoalkyl, -(CH2)o-40(Ci-3 alkyl), C3-6 cycloalkyl, -(CH 2 )i- 3 C(0)NR x R x , -CH 2 (C 3 -6 cycloalkyl), -CH 2 (phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl;
  • each R 2a is independently H, halo, -CN, -NR X R X , Ci-6 alkyl, C 1-3 fluoroalkyl, C 1-3
  • R2b is R2 or R2 a ;
  • R2c is R2 or R2 a ; provided that one of R2b and R2c is R2, and the other of R2b and R2c is R2 a ; R 3 is
  • Ci-6 alkyl Ci-6 fluoroalkyl, Ci-6 hydroxyalkyl, C1-3 cyanoalkyl, -(CH2)o-40(Ci-3 alkyl), -(CH 2 CH 2 0)2-30(Ci-3 alkyl), -CH 2 CH 2 NR X R X , -CR x R x C(0)OH,
  • Li is a bond, -(CRxRx - -(CRxRx O- -CRxRxCCO)-,
  • A is adamantanyl, azepanyl, azetidinyl, C3-6 cycloalkyl, diazepanyl, dihydroinonyl,
  • each Rx is independently H or -CH3;
  • Rz is H, Ci-2 alkyl, or C1-2 fluoroalkyl
  • n is zero, 1, 2, 3, or 4;
  • n zero, 1, 2, or 3.
  • odiment provides a compound of Formula (I) or a salt thereof, wherein Y
  • Ri, R2, R2a, R3, R4, R5, m, and n are defined in the first aspect.
  • Ri is -CH(CH3)2.
  • Ri, R2, R2a, R3, R4, R5, m, and n are defined in the first aspect.
  • Ri is -CH(CH3)2.
  • Ri is -CH(CH3)2.
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein Y
  • Ri is -CH(CH3)2.
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein Y
  • Ri is -CH(CH 3 ) 2 .
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein Y
  • Rl, R 2 , R2a, R2b, R2c, R3, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which Ri is -CH(CH 3 )2.
  • odiment provides a compound of Formula (I) or a salt thereof, wherein Y
  • Ri is and Ri, R2, R2a, R2b, R2c, R3, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which R2b is R. Also included in this embodiment are compounds in which R2b is R2a. Additionally, included in this embodiment are compounds in which Ri is -CH(C]3 ⁇ 4)2.
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein Ri is H, CI, -CN, Ci-4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxy-fluoroalkyl, C3-6 cycloalkyl, -CH2(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), or tetrahydropyranyl; and R2, R2a, R2b, R2c, R3, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which Ri is H, C1-4 alkyl, C1-3 fluoroalkyl, or C3-6 cycloalkyl. Also included in this embodiment are compounds in which Ri is -CH2CH3 or -CH(CH3)2. Additionally, included in this embodiment are compounds in which Ri is -CH(CH3)2.
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein
  • R2 is Ci-4 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-2 aminoalkyl, -(CH2)o-40(Ci-2 alkyl), C3-6 cycloalkyl, -(CH 2 )i- 2 C(0)NR x R x , -CH 2 (C 3 -6 cycloalkyl), -CH 2 (phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl; and Y, Ri, R2a, R2b, R2c, R3, R4, R5, Rx, m, and n are defined in the first aspect.
  • R 2 is CM alkyl, C1-2 fluoroalkyl, CM hydroxyalkyl, -(CH 2 )i-30CH 3 , C3-6 cycloalkyl, -CH 2 C(0)NR x R x , -CH 2 (C3-e cycloalkyl), -CH 2 (phenyl), tetrahydrofuranyl, or phenyl.
  • R2 is -CH3,
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein Ri is -CH(CH 3 ) 2 ; R2 is -CH 3 , -CH2CH3, -CH(CH 3 ) 2 , -CH 2 CH(CH 3 )2, -CH2CH2OH, -CH2CH2CH2OH, -CH 2 C(CH 3 )20H, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2(cyclopropyl), -CH2(phenyl), -CH2C(0)NH2, tetrahydrofuranyl, or phenyl; and R.2b, R2c, R3, R4, R5, Rx, m, and n are defined in the first aspect. Included in this
  • R2a is independently H, F, CI, -CN, -NR X R X , Ci-6 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkoxy, -(CH 2 )o- 2 0(C i-3 alkyl), -(CH 2 )o-3C(0)NR x Rx,
  • each R2a is independently H, F, CI, -CN, -NH2, C 1-5 alkyl, -CF 3 , -CH2OH, -OCH3, -CH2OCH3, -CH 2 CH 2 (cyclopropyl), -C(0)OCH 3 , -C(0)N(CH 3 ) 2 , -C(0)NH(CH 2 CH 2 CH 3 ),
  • R2a is independently H, F, CI, -CN, -NR X R X , Ci-6 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkoxy, -(CH 2 )o- 2 0(C i-3 alkyl), -(CH 2 )o-3C(0)NR x Rx,
  • each R y is independently F, CI, -CN, C1-2 alkyl, C1-2 alkoxy, -NR x C(0)(C i- 2 alkyl), -C(0)NR x R x , C3-6 cycloalkyl, or morpholinyl; and Y, Ri, R2, R2b, R2c, R3, R4, R5, Rx, m, and n are defined in the first aspect.
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is -Li-A; and Y, Ri, R2, R2a, R2t>, R2c, R4, R5, Li, A, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each Li is a bond,
  • R3 is -Li-A
  • Li is a bond, -(CR x R x )i- 2 - -CR x R x C(0)-, -C(0)(CR x R x )o-i- -C(0)0- or -S(0)2(CR x R x )o-2-
  • A is azetidinyl, C3-6 cycloalkyl, dioxotetrahydrothiophenyl, oxetanyl, phenyl, piperidinyl,, pyrazolyl, pyrazolidinonyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, or triazolyl, each substituted with zero, 1, or 2 R.3 a
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is -CH2(methyl triazolyl), -CH2(trifluoromethyl phenyl), -CH2(difluoromethyl, fluorophenyl), -CH2(fluoro, chlorophenyl), -CH2(difluorocyclopropyl),
  • -C(0)CH 2 (pyrrolidinonyl), -C(0)CH 2 (pyrrolidinyl), -C(0)0(methyl pyrrolidinyl), -S(0)2CH2CH2(pyrrolidinyl), -CH2(hydroxytetrahydropyranyl), or a cyclic group selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinonyl,
  • R3 is H, Ci-6 alkyl, Ci-6 fluoroalkyl, Ci-6 hydroxyalkyl, C 1-3 cyanoalkyl, -(CH2)o-40(Ci-3 alkyl), -(CH 2 CH 2 0)2-30(Ci-3 alkyl), -CH 2 CH 2 NR X R X , -CR x R x C(0)OH,
  • each R3a is independently F, CI, -OH, -NH2, C1-3 alkyl, C1-2 fluoroalkyl, or -C(0)NR x R x . Also included are compounds in which each R3a is independently F, -OH, -CH 3 , -CH(CH 3 ) 2 , -CF 3 , or -C(0)NH 2 .
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R5 is independently F, -CN, -CH3, -CF3, or -OCH3; and Ri, R2, R2a, R2t>, R2c, R3, R4, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each R5 is independently F, -CH3, or -CF3. Also included in this embodiment are compounds in which R5 is F and n is zero or 1.
  • R5 is F; m is zero; n is zero or 1; and R2, R2a, R3, and
  • R4 are defined in the first aspect. Included in this embodiment are compounds in which is zero.
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein
  • Ri is H, Ci-4 alkyl or C1-3 fluoroalkyl, or C3-6 cycloalkyl;
  • R2 is C1-4 alkyl, C1-2 fluoroalkyl, CM hydroxyalkyl, -(CH 2 )i-30CH 3 , C3-6 cycloalkyl, -CH 2 C(0)NR x R x , -CH 2 (C 3 -6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, or phenyl; each R2a is independently H, F, CI, -CN, -NR x Rx, Ci-6 alkyl, C1-2 fluoroalkyl, C1-3 hydroxyalkyl, -(CH 2 )o- 2 0(Ci-2 alkyl), -(CH 2 )o- 2 C(0)NR x R x , -(CH 2 )i-3(cyclopropyl), -C(0)0(Ci- 2 alkyl), -
  • Li is a bond, -(CR x R x )i- 2 - -CR x R x C(0)-, -C(0)(CR x R x )o-i-, -C(0)0- or -S(0) 2 (CR x R x )o- 2 -;
  • A is azetidinyl, C3-6 cycloalkyl, dioxotetrahydrothiophenyl, oxetanyl, phenyl, piperidinyl,, pyrazolyl, pyrazolidinonyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl,
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein Ri is -CH 2 CH 3 or -CH(CH 3 ) 2 ; R 2 is -CH3, -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CHF 2 , -CH 2 CF 3 ,
  • each R 2a is independently H, F, CI, -CN, -NH 2 , C1-5 alkyl, -CF3, -CH 2 OH, -OCH3, -CH 2 OCH 3 , -CH 2 CH 2 (cyclopropyl), -C(0)OCH 3 , -C(0)N(CH 3 ) 2 ,
  • Ra> is R 2 or R 2a ;
  • R 2c is R 2 or R 2a ; provided that one of Ra> and R 2c is R 2 , and the other of Ra> and R 2c is R 2a ;
  • R3 is H, -CH3,
  • -CH 2 (tetrahydropyranyl), -CH 2 C(0)(hydroxypyrrolidinyl), -CH 2 C(0)(pyrazolidinonyl), -CH 2 C(0)(pyrrolidinyl), -CH 2 (dimethyl pyrazolyl), -CH 2 (methyl pyrazolyl),
  • -CH 2 (pyrazolyl), -CH 2 (cyclopropyl), -CH 2 (tetrahydrofuranyl), -CH 2 (z-propyl pyrazolyl), -CH 2 ( «-propyl pyrazolyl), -CH(CH 3 )(methyl pyrazolyl),
  • -CH 2 (hydroxytetrahydropyranyl), or a cyclic group selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, piperidinyl, and dioxotetrahydrothiophenyl, each substituted with zero, 1, or 2 R 3a ; each R 3a is independently F, -OH, -CH 3 , -CH(CH 3 ) 2 , -CF 3 , or -C(0)NH 2 ; R5 is F; m is zero; and n is zero or 1.
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is selected from 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methylpyridin-2(lH)-on (1); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (2); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3,6- trimethylpyridin-2(lH)-one (3);5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,6- dimethylpyridin-2(lH)-one (6); 5-(3-isopropyl-5-(piperidin-4-yl)-
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is selected from 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methylpyrazin-2(lH)-one (4); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyrazin-2(lH)-one (12); 2-(4-(2-(4,6-dimethyl-5-oxo-4,5-dihydropyrazin-2-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (115); 5-(3-isopropyl- 5-(l-methylpiperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is selected from 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2- methylpyridazin-3(2H)-one (5); 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2,5- dimethylpyridazin-3(2H)-one (10); 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2,4- dimethylpyridazin-3(2H)-one (11); 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)- 2,4,5-trimethylpyridazin-3(2H)-one (17); 2-ethyl-6-(3-isopropyl-5-(
  • One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyrimidine-2,4(lH,3H)-dione (21).
  • references made in the singular may also include the plural.
  • references made in the singular may also include the plural.
  • “a” and “an” may refer to either one, or one or more.
  • a compound of Formula (I) includes a compound of Formula (I) and two or more compounds of Formula (I).
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • cyano refers to the group -CN.
  • amino refers to the group -NH2.
  • alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g.
  • n-butyl i-butyl, sec-butyl, and i-butyl
  • pentyl e.g., n-pentyl, isopentyl, neopentyl
  • n-hexyl 2-methylpentyl, 2-ethylbutyl, 3 -methylpentyl, and 4- methylpentyl.
  • Ci-6 alkyl denotes straight and branched chain alkyl groups with one to six carbon atoms.
  • fluoroalkyl as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms.
  • C1-4 fluoroalkyl is intended to include Ci, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms.
  • Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.
  • chloroalkyl as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more chlorine atoms.
  • C1-4 chloroalkyl is intended to include Ci, C2, C3, and C4 alkyl groups substituted with one or more chlorine atoms.
  • Representative examples of fluoroalkyl groups include, but are not limited to, -CCI3 and -CH2CCI3.
  • cyanoalkyl includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups.
  • cyanoalkyl includes -CH2CN, -CH2CH2CN, and CM cyanoalkyl.
  • aminoalkyl includes both branched and straight-chain saturated alkyl groups substituted with one or more amino groups.
  • aminoalkyl includes -CH2NH2, -CH2CH2NH2, and Ci-4 aminoalkyl.
  • hydroxyalkyl includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups.
  • hydroxyalkyl includes -CH2OH, -CH2CH2OH, and C M hydroxyalkyl.
  • hydroxy-fluoroalkyl includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms.
  • hydroxy-fluoroalkyl includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms.
  • cycloalkyl refers to a group derived from a non- aromatic monocyclic or poly cyclic hydrocarbon molecule by removal of one hydrogen atom from a saturated ring carbon atom.
  • Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl.
  • the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group may contain.
  • C3-C6 cycloalkyl denotes cycloalkyl groups with three to six carbon atoms.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (-OCH3).
  • -OCH3 methoxy group
  • C1-3 alkoxy denotes alkoxy groups with one to three carbon atoms.
  • fluoroalkoxy and "-O(fluoroalkyl)" represent a fluoroalkyl group as defined above attached through an oxygen linkage (-0-).
  • oxygen linkage -0-
  • fluoroalkoxy is intended to include Ci, C2, C3, and C4 fluoroalkoxy groups.
  • alkoxy alkoxy refers to an alkoxy group attached to the parent molecular moiety through an alkoxy group, for example, methoxymethoxy group (-OCH2OCH3).
  • alkoxyalkoxy denotes alkoxy groups with one to four carbon atoms.
  • benzyl refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group.
  • the phenyl ring may be unsubstituted or may contain one or more substituents as valence allows.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the compounds of Formula (I) can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of Formula (I) as amorphous solids.
  • solvates e.g., hydrates of the compounds of Formula (I) are also within the scope of the present invention.
  • solvate means a physical association of a compound of Formula (I) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.
  • compounds of Formula (I) subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formula (I) ("substantially pure"), which is then used or formulated as described herein.
  • substantially pure compounds of Formula (I) are also contemplated herein as part of the present invention.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the present invention is intended to embody stable compounds.
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor to TLR7/8/9, or effective to treat or prevent autoimmune and/or inflammatory disease states, such as SLE, IBD, multiple sclerosis (MS), Sjogren's syndrome, and rheumatoid arthritis.
  • autoimmune and/or inflammatory disease states such as SLE, IBD, multiple sclerosis (MS), Sjogren's syndrome, and rheumatoid arthritis.
  • treating cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease- state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
  • the compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium (D) and tritium (T).
  • Isotopes of carbon include 1 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • methyl (- CH3) also includes deuterated methyl groups such as -CD3.
  • the human immune system has evolved to defend the body from microorganisms, viruses, and parasites that can cause infection, disease or death. Complex regulatory mechanisms ensure that the various cellular components of the immune system target the foreign substances or organisms, while not causing permanent or significant damage to the individual. While the initiating events are not well understood at this time, in autoimmune disease states the immune system directs its inflammatory response to target organs in the afflicted individual.
  • autoimmune diseases are typically characterized by the predominate or initial target organ or tissues affected; such as the joint in the case of rheumatoid arthritis, the thyroid gland in the case of Hashimoto's thyroiditis, the central nervous system in the case of multiple sclerosis, the pancreas in the case of type I diabetes, and the bowel in the case of inflammatory bowel disease.
  • the compounds of the invention inhibit signaling through Toll-like receptor 7, or 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Accordingly, compounds of Formula (I) have utility in treating conditions associated with the inhibition of signaling through one or more of TLR7, TLR8, or TLR9. Such conditions include TLR7, TLR8, or TLR9 receptor associated diseases in which cytokine levels are modulated as a consequence of intracellular signaling.
  • the terms "treating” or “treatment” encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease state, i.e., arresting its development; and/or (c) achieving a full or partial reduction of the symptoms or disease state, and/or alleviating, ameliorating, lessening, or curing the disease or disorder and/or its symptoms.
  • the compounds of Formula (I) are useful in treating TLR7, TLR8, or TLR9 family receptor associated diseases, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis; auto-inflammatory diseases including CAPS, TRAPS, FMF, adult onset Still's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myelogenous leukemia,
  • angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; infectious diseases such as sepsis, septic shock, and Shigellosis; neurodegenerative diseases such as Alzheimer's disease,
  • Parkinson's disease cerebral ischemias or neurodegenerative disease caused by traumatic injury, oncologic and viral diseases such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS, respectively.
  • the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs.
  • Preferred methods of treatment are those wherein the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.
  • preferred methods of treatment are those wherein the condition is selected from ischemia reperfusion injury, including cerebral ischemia reperfusions injury arising from stroke and cardiac ischemia reperfusion injury arising from myocardial infarction.
  • Another preferred method of treatment is one in which the condition is multiple myeloma.
  • the compounds of Formula (I) are useful in treating cancer, including Waldenstrom's Macroglobulinemia (WM), diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneous diffuse large B cell lymphoma, and primary CNS lymphoma.
  • WM Waldenstrom's Macroglobulinemia
  • DLBCL diffuse large B cell lymphoma
  • CLL chronic lymphocytic leukemia
  • cutaneous diffuse large B cell lymphoma including cutaneous diffuse large B cell lymphoma, and primary CNS lymphoma.
  • TLR7, TLR8, or TLR9 inhibitors of the present invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin
  • TLR7/8/9 associated conditions include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by cancer, dental pain and arthritis pain.
  • inventive compounds also may be used to treat veterinary viral infections, such as lentivirus infections, including, but not limited to equine infectious anemia virus; or retrovirus infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.
  • the present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically-effective amount of at least one compound of Formula (I) or a salt thereof.
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit autoimmune disease or chronic inflammatory disease.
  • TLR7, TLR8, or TLR9 associated conditions may comprise administering compounds of Formula (I) alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions.
  • therapeutically effective amount is also intended to include an amount of the combination of compounds claimed that is effective to inhibit TLR7, TLR8, or TLR9 and/or treat diseases associated with TLR7, TLR8, or TLR9.
  • Such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®); anti-malarials such as hydroxychloroquine; cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor,
  • therapeutic agents when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians ' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • PDR Physicians ' Desk Reference
  • such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the
  • the present invention also provides pharmaceutical compositions capable of treating TLR7/8/9 receptor-associated conditions, including IL-1 family receptor-mediated diseases as described above.
  • inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g. , excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • pharmaceutical additives e.g. , excipients, binders, preservatives, stabilizers, flavors, etc.
  • compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent- containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g. , stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable
  • Compounds in accordance with Formula (I) can be administered by any means suitable for the condition to be treated, which can depend on the need for site-specific treatment or quantity of Formula (I) compound to be delivered.
  • compositions comprising a compound of Formula (I) and one or more non-toxic, pharmaceutically - acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier” materials) and, if desired, other active ingredients.
  • carrier non-toxic, pharmaceutically - acceptable carriers and/or diluents and/or adjuvants
  • the compounds of Formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds and compositions of the present invention may, for example, be administered orally, mucosally, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose.
  • the mixture may contain additional components such as a lubricating agent, e.g. magnesium stearate and a disintegrating agent such as crospovidone.
  • the carrier mixture may be filled into a gelatin capsule or compressed as a tablet.
  • the pharmaceutical composition may be administered as an oral dosage form or an infusion, for example.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg.
  • a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods.
  • any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations.
  • exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs.
  • Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration.
  • a pharmaceutical composition in accordance with the invention can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.
  • a tablet can, for example, be prepared by admixing at least one compound of Formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.
  • excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc.
  • inert diluents such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate
  • granulating and disintegrating agents such as, for example
  • a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period.
  • exemplary water soluble taste masking materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose.
  • Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.
  • Hard gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.
  • at least one inert solid diluent such as, for example, calcium carbonate; calcium phosphate; and kaolin.
  • Soft gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.
  • at least one water soluble carrier such as, for example, polyethylene glycol
  • at least one oil medium such as, for example, peanut oil, liquid paraffin, and olive oil.
  • An aqueous suspension can be prepared, for example, by admixing at least one compound of Formula (I) with at least one excipient suitable for the manufacture of an aqueous suspension.
  • excipients suitable for the manufacture of an aqueous suspension include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, alginic acid, poly vinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, poly oxy ethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol;
  • condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as, for example, polyoxy ethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate.
  • An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n- propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.
  • Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin.
  • An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol.
  • at least one of the sweetening agents already described hereinabove, and/or at least one flavoring agent can be added to the oily suspension.
  • An oily suspension can further contain at least one preservative, including, but not limited to, for example, an antioxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.
  • Dispersible powders and granules can, for example, be prepared by admixing at least one compound of Formula (I) with at least one dispersing and/or wetting agent; at least one suspending agent; and/or at least one preservative.
  • Suitable dispersing agents, wetting agents, and suspending agents are as already described above.
  • Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid.
  • dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.
  • An emulsion of at least one compound of Formula (I) thereof can, for example, be prepared as an oil-in-water emulsion.
  • the oily phase of the emulsions comprising compounds of Formula (I) may be constituted from known ingredients in a known manner.
  • the oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • Suitable emulsifying agents include, but are not limited to, for example, naturally-occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and/or an antioxidant.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the compounds of Formula (I) can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form.
  • injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in- water microemulsions; and aqueous or oleaginous suspensions.
  • Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or mi cellar solubilization (i.e. Tween 80).
  • suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or mi cellar solubilization (i.e. Tween 80).
  • the sterile injectable preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1 ,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of inj ectables.
  • a sterile injectable oil-in- water microemulsion can, for example, be prepared by 1) dissolving at least one compound of Formula (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Formula (I) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.
  • an oily phase such as, for example, a mixture of soybean oil and lecithin
  • combining the Formula (I) containing oil phase with a water and glycerol mixture and 3) processing the combination to form a microemulsion.
  • a sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art.
  • a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1 ,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.
  • Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol poly ethylenegly col 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,
  • Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • the pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
  • the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings.
  • Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
  • the amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.
  • the daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.
  • the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • compositions of this invention comprise at least one compound of Formula (I) and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle.
  • Alternate compositions of this invention comprise a compound of the Formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the present invention also encompasses an article of manufacture.
  • article of manufacture is intended to include, but not be limited to, kits and packages.
  • the article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a cardiovascular and/or inflammatory disorder (as defined previously).
  • the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat
  • the article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.
  • the first container is a receptacle used to hold a pharmaceutical composition.
  • This container can be for manufacturing, storing, shipping, and/or individual/bulk selling.
  • First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g. , for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
  • the second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
  • the package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container.
  • the package insert is located on the outside of the second container.
  • the package insert is physically attached via tape, glue, staple, or another method of attachment.
  • it can be adjacent to or touching the outside of the second container without being physically attached.
  • the package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container.
  • the information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g. , the United States Food and Drug
  • the package insert specifically recites the indications for which the pharmaceutical composition has been approved.
  • the package insert may be made of any material on which a person can read information contained therein or thereon.
  • the package insert is a printable material (e.g. , paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g. , printed or applied).
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
  • the compounds of this invention may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • compounds of Formula I may be produced, starting with the substituted 5-haloindoles (2).
  • 2 can be prepared from the 3-formyl indoles (via reduction) or from the 3-H indoles, via alkylation.
  • Transition metal catalyzed cross coupling of 2 and boronate 3 followed by olefin reduction and bromination affords 4, which can then be converted to the boronic ester 5.
  • Transition metal catalyzed cross coupling of 5 with aryl halide 6 followed by Boc deprotection yields 7. Alkylation of 7 leads to the production of the compounds of Formula I.
  • X can be CI, Br, I or OTf
  • QC-ACN-AA-XB Column: Waters Acquity UPLC BEH C 18, 2.1 x 50 mm, 1. particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;
  • Mobile Phase B 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.
  • QC-ACN-TFA-XB Column: Waters Acquity UPLC BEH C 18, 2.1 x 50 mm, 1.7- ⁇ particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.
  • Method Al L3 Acquity: Column: (LCMS) UPLC BEH C18, 2.1 x 50 mm, 1.7 ⁇ particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98%B (to 1.5 min) 98%-2% B (to 1.6 min); Gradient Time: 1.6 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1 : UV at 220 nm; Detector 2: MS (ESI + ).
  • Method Bl L2 Aquity(4); Column: (LCMS) UPLC BEH C 18, 2.1 x 50 mm, 1.7 ⁇ particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98%B (to 1.5 min) 98%-2% B (to 1.5 min); Gradient Time: 1.8 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1 : UV at 220 nm; Detector 2: MS (ESI + ).
  • Method CI SCP Column: Waters Acquity UPLC BEH CI 8, 2.1 x 50 mm, 1.7- ⁇ particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;
  • Mobile Phase B 95:5 acetonitrile:water with 10 mM ammonium acetate. Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
  • Method Dl SCP Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7- ⁇ particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
  • Method D2 SCP: Column: XBridge CI 8, 19 x 200 mm, 5- ⁇ particles;
  • Method D3 SCP Column: XBridge CI 8, 19 x 200 mm, 5- ⁇ particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 6-46% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Detection: UV at 220 nm.
  • Method El iPAC Column: Waters Xbridge CI 8 4.6 x 50 mm 5 um particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate. Temperature: 50 °C; Gradient: 0- 100%) B over 1 minute; Flow: 4 mL/min; Detection: UV at 220 nm.
  • Method Fl iPAC Column: Waters Acquity BEH C18 2.1x50 mm 1.7- ⁇ particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0- 100% B over 2.20 minutes; Flow: 0.800 mL/min; Detection: UV at 220 nm.
  • (E) Column: Ascentis Express CI 8 (50x2. l)mm, 2.7 ⁇ ; Mobile Phase A: 5:95 acetonitrile: water with 10 mM NEUOAc; Mobile Phase B: 95:5 acetonitrile: water with 10 mM NELtOAc; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min.
  • Template 1 tert-but -(2-bromo-3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate
  • Template 2 tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indol-5-yl)piperi dine- 1 -carboxy late
  • Lithium diisopropylamide (169 ⁇ , 0.339 mmol) was added dropwise to the vial (via a syringe through the septum cap) over - 15 min.
  • the reaction mixture was stirred at -20 °C for 1 h, then allowed to slowly warm to 10 °C.
  • the reaction was quenched by addition of 1 M KHSO4 (2 mL), and the resulting mixture was extracted with EtOAc (3x2 mL). The combined organic exacts were dried over Na2S04, and filtered. Excess solvent was evaporated off under an N2 stream.
  • Fragment 1 5-bromo-l,3-dimethylpyridin-2(lH)-one
  • Fragment 3 5-Bromo-3-methyl-l -phenylpyridin-2(lH)-
  • Fragment 5 5-bromo-3-chloro-l ,6-dimethylpyridin-2(lH)-one
  • Fragment 20 5-chloro-l,3-dimethylpyrazin-2(lH)-one
  • reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and washed with aqueous 10% NaF solution (2x10 mL) and saturated aqueous NaCl solution (1x10 mL), dried (Na2S04), filtered and concentrated.
  • Fragment 22 6-Chloro-2-ethyl-4 -dimethylpyridazin-3(2H)-one
  • Fragment 24 5-Bromo-3-methoxy-l ,6-dimethylpyridin-2(lH)-one
  • Fragment 25 5-Bromo-3-methoxy-l ,4-dimethylpyridin-2(lH)-one
  • 2nd Generation XPhos precatalyst (3.99 mg, 5.07 ⁇ ) was added to the reaction mixture.
  • the reaction mixture was placed under a nitrogen atmosphere and stirred at 60 °C for 20 h.
  • the aqueous phase was removed, and excess solvent was evaporated from the organic phase.
  • the residue was taken up in DCM (3 mL) and purified by flash chromatography on a 4 g silica column, eluting with ethyl acetate and hexanes on an Isco Rf instrument. The product did not elute, so the column was then eluted with 1 -15% MeOH in dichloromethane.
  • Fragment 29 5-Bromo-3-chloro-l,4-dimethylpyridin-2(lH)-one
  • Fragment 30 5-Bromo-l-(2-hydroxy-2-methylpropyl)-3-methylpyridin-2(lH)-one
  • the vial was fitted with a Teflon lined septum cap.
  • the vial was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The evacuation procedure was repeated three times.
  • the needle was removed and the vial was heated at 65 °C for 18 h.
  • the reaction mixture was concentrated to dryness and treated with TFA (1 mL) for 30 min to facilitate the removal of the tert-butyloxycarbonyl group.
  • the reaction mixture was re- concentrated to dryness and re-dissolved in DMF (2 mL).
  • the vial was fitted with a Teflon lined septum cap.
  • the vial was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The evacuation procedure was repeated three times.
  • the needle was removed and the vial was heated at 65 °C for 2 h.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaCl solution (10 mL), dried (Na2S04), filtered and concentrated to afford crude material.
  • the purified tert-butyl 4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidine-l-carboxylate was dissolved in DCM (10 mL) and treated with TFA (10 mL). The reaction mixture was stirred for 30 min and concentrated to dryness. The residue was treated with saturated aqueous ammonium hydroxide (20 mL) and stirred for 30 min.
  • the vial was fitted with a Teflon lined septum cap.
  • the vial was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times.
  • the needle was removed and the vial was heated at 65 °C for 20 h.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and washed with saturated aqueous NaCl solution (5 mL), dried (Na2S04), filtered and concentrated to afford crude material.
  • the vial was fitted with a Teflon lined septum cap and the system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 100 °C for 6 h. Additional Pd catalyst ( ⁇ 1 mg) and tetramethyl tin (20 ⁇ ) were added and the reaction mixture was heated for an additional 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL) and washed with 10% aqueous LiCl solution (3x2 mL), dried (Na2S04), filtered and concentrated.
  • the suspension was stirred and kept under a nitrogen atmosphere while triethylsilane (0.051 mL, 0.322 mmol) was added dropwise via syringe over ⁇ 5 min.
  • the reaction mixture was stirred at room temperature for 30 min.
  • the reaction mixture was filtered through celite, flushing with MeOH. Excess solvent was evaporated from the reaction mixture to yield a pale yellow oil.
  • reaction mixture was partitioned between water and ethyl acetate (3 mL total volume), separated, and the aqueous phase was extracted with additional ethyl acetate (2x1 mL). Excess solvent was evaporated from the combined organic extracts. The resulting residue was deprotected with 2: 1 trifluoroacetic acid/dichloromethane (1.2 mL, 0.025 mmol) for 45 min. Excess solvent was evaporated from the reaction mixture.
  • the material was further purified via preparative LC/MS with the following conditions: Column: XBridge CI 8, 19 x 200 mm, 5-im particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifiuoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifiuoroacetic acid; Gradient: 7- 47% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.
  • Methyl 5-bromo-2-oxo-l,2-dihydropyridine-3-carboxylate (Combi-Blocks, CAS: 120034-05-1, 0.100 g, 0.431 mmol) was dissolved in THF (4.31 mL) and added dropwise to a 0 °C solution of lithium aluminum hydride (0.082 g, 2.155 mmol) in THF (4.31 mL).
  • Method A A mixture containing 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (75 mg, 0.206 mmol), 2-chloro-N,N-dimethylacetamide (0.027 mL, 0.258 mmol) and K2CO3 (86 mg, 0.619 mmol) was suspended in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was treated with water (4 mL) and stirred for 30 min.
  • the reaction mixture was stirred for 20 h, diluted with ethyl acetate (5 mL) and washed with aqueous IN NaOH (2X2 mL) and saturated aqueous NaCl solution (lxl mL), filtered through a plug of Na2S04 and concentrated. The residue was dissolved in DCM (1 mL) and treated with TFA (0.5 mL). The reaction mixture was concentrated. The sample was dissolved in DMF (2 mL), filtered through an Acrodisc, 13 mm, 0.45 micron nylon membrane syringe filter. The crude material was purified via preparative LC/MS.
  • the reaction mixture was stirred for 20 h, diluted with ethyl acetate (4 mL) and washed with IN NaOH (2x1 mL) and saturated aqueous NaCl solution (1 mL) and concentrated. The residue was treated with TFA (1 mL) for 30 min to facilitate the removal of the Boc groups. The reaction mixture was re-concentrated to dryness and re-dissolved in DMF (2 mL). The sample was filtered through an Acrodisc, 13 mm, 0.45 micron nylon membrane syringe filter. The crude material was purified via preparative LC/MS.
  • Example 309 The following examples were prepared in a manner similar to Example 309, using the indicated starting material.
  • the pharmacological properties of the compounds of this invention may be confirmed by a number of biological assays.
  • the exemplified biological assays, which follow, have been carried out with compounds of the invention.
  • HEK-BlueTM-cells (Invivogen) overexpressing human TLR7, TLR8 or TLR9 receptors were used for screening inhibitors of these receptors using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene under the control of the IFN- ⁇ minimal promoter fused to five NF- ⁇ and AP-1 -binding sites. Briefly, cells are seeded into Greiner 384 well plates (15000 cells per well for TLR7, 20,000 for TLR8 and 25,000 for TLR9) and then treated with test compounds in DMSO to yield a final dose response concentration range of 0.05 nM - 50 ⁇ .
  • SEAP secreted embryonic alkaline phosphatase
  • the cells are then stimulated with a TLR7 ligand (gardiquimod at a final concentration of 7.5 ⁇ ), TLR8 ligand (R848 at a final concentration of 15.9 ⁇ ) or TLR9 ligand (ODN2006 at a final concentration of 5 nM) to activate NF- ⁇ and AP-1 which induce the production of SEAP.
  • TLR7 ligand gardiquimod at a final concentration of 7.5 ⁇
  • TLR8 ligand R848 at a final concentration of 15.9 ⁇
  • ODN2006 TLR9 ligand
  • SEAP levels are determined with the addition of HEK-BlueTM Detection reagent (Invivogen), a cell culture medium that allows for detection of SEAP, according to manufacturer's specifications. The percent inhibition is determined as the % reduction in the HEK-Blue signal present in wells treated with agonist plus DMSO alone compared to wells treated with a known inhibitor.

Abstract

Disclosed are compounds of Formula (I) or a salt thereof, wherein: Y is Formula (II), or Formula (III); R1, R2, R2a, R2b, R2c, R3, R4,R5, m, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.

Description

SUBSTITUTED INDOLE COMPOUNDS USEFUL AS INHIBITORS OF TLR7/8/9
DESCRIPTION
The present invention generally relates to substituted indole compounds useful as inhibitors of signaling through Toll-like receptor 7, 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Provided herein are substituted indole compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to TLR modulation, such as inflammatory and autoimmune diseases, and methods of inhibiting the activity of TLRs in a mammal.
Toll/IL-1 receptor family members are important regulators of inflammation and host resistance. The Toll-like receptor family recognizes molecular patterns derived from infectious organisms including bacteria, fungi, parasites, and viruses (reviewed in Kawai, T. et al, Nature Immunol. , 1 1 :373-384 (2010)). Ligand binding to the receptor induces dimerization and recruitment of adaptor molecules to a conserved cytoplasmic motif in the receptor termed the Toll/IL-1 receptor (TIR) domain. With the exception of TLR3, all TLRs recruit the adaptor molecule MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, J.E. et al, Nature Rev. Immunol , 10: 89-102 (2010)).
Toll-like receptors (TLRs) are a family of evolutionarily conserved,
transmembrane innate immune receptors that participate in the first-line defense. As pattern recognition receptors, the TLRs protect against foreign molecules, activated by pathogen associated molecular patterns (PAMPs), or from damaged tissue, activated by danger associated molecular patterns (DAMPs). A total of 13 TLR family members have been identified, 10 in human, that span either the cell surface or the endosomal compartment. TLR7-9 are among the set that are endosomally located and respond to single-stranded RNA (TLR7and TLR8) or unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs (TLR9).
Activation of TLR7/8/9 can initiate a variety of inflammatory responses (cytokine production, B cell activation and IgG production, Type I interferon response). In the case of autoimmune disorders, the aberrant sustained activation of TLR7/8/9 leads to worsening of disease states. Whereas overexpression of TLR7 in mice has been shown to exacerbate autoimmune disease, knockout of TLR7 in mice was found to be protective against disease in lupus-prone MRL/lpr mice. Dual knockout of TLR7 and 9 showed further enhanced protection.
As numerous conditions may benefit by treatment involving modulation of cytokines, IFN production and B cell activity, it is immediately apparent that new compounds capable of modulating TLR7 and/or TLR8 and/or TLR9 and methods of using these compounds could provide substantial therapeutic benefits to a wide variety of patients.
The present invention relates to a new class of substituted indole compounds found to be effective inhibitors of signaling through TLR7/8/9. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.
SUMMARY OF THE INVENTION
The present invention provides compounds of Formula (I) that are useful as inhibitors of signaling through Toll-like receptor 7, 8, or 9 and are useful for the treatment of proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
The present invention also provides a method for inhibition of Toll-like receptor 7, 8, or 9 comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
The present invention provides a method for treating inflammatory and autoimmune diseases. Particular, inflammatory and autoimmune diseases include, but are not limited to, Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, adult onset Still's disease, systemic onset juvenile idiopathic arthritis, multiple sclerosis.
DETAILED DESCRIPTION
The first aspect of the present invention provides at least one compound of
Figure imgf000004_0001
Ri is H, CI, -CN, CM alkyl, C1-3 fluoroalkyl, C 1-3 hydroxy-fluoroalkyl, -CRZ=CH2, C3-6 cycloalkyl, -CH2(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), or tetrahydropyranyl;
R2 is Ci-6 alkyl, C1-3 fluoroalkyl, Ci-6 hydroxyalkyl, C 1-3 aminoalkyl, -(CH2)o-40(Ci-3 alkyl), C3-6 cycloalkyl, -(CH2)i-3C(0)NRxRx, -CH2(C3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl;
each R2a is independently H, halo, -CN, -NRXRX, Ci-6 alkyl, C 1-3 fluoroalkyl, C 1-3
hydroxyalkyl, C1-3 fluoroalkoxy, -(CH2)o-20(Ci-3 alkyl), -(CH2)o-3C(0)NRxRx, -(CH2)i-3(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), -C(0)NRx(Ci-3 alkyl), -CRX=CRXRX,
Figure imgf000004_0002
cycloalkyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry; each Ry is independently F, CI, -CN, C 1-3 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy,
-NRxC(0)(Ci-3 alkyl), -C(0)NRxRx, C3-6 cycloalkyl, piperidinyl, or nK^holinyl; R2b is R2 or R2a;
R2c is R2 or R2a; provided that one of R2b and R2c is R2, and the other of R2b and R2c is R2a; R3 is
(a) -Li-A; or
(b) H, Ci-6 alkyl, Ci-6 fluoroalkyl, Ci-6 hydroxyalkyl, C1-3 cyanoalkyl, -(CH2)o-40(Ci-3 alkyl), -(CH2CH20)2-30(Ci-3 alkyl), -CH2CH2NRXRX, -CRxRxC(0)OH,
-(CRxRx)o-2C(0)NRxRx, -CH2C(0)NRx(Ci-3 alkyl), -CH2C(0)NRx(Ci-4
hydroxyalkyl), -(CRxRx)o-2S(0)2(Ci-3 alkyl), -C(0)(Ci-3 alkyl), -C(0)(Ci-3 fluoroalkyl), -C(0)CRxRxNRxRx, -C(0)(Ci-e hydroxyalkyl), or -NRxC(0)(Ci-3 alkyl);
Li is a bond, -(CRxRx -
Figure imgf000005_0001
-(CRxRx O- -CRxRxCCO)-,
-(CRxRx)2NRx(CRxRx)o-i-, -CRxRxC(0)NRx(CRxRx)o-4-, -C(0)(CRxRx)o-3- -C(0)(CRxRx)o-2NRx(CRxRx)o-2-, -C(0)(CRxRx)o-2NRx(CRxRx)i-2CRx(OH)-, -C(0)(CRxRx)i-2C(0)NRx-, -(CRxRx)o-2C(0)NRx(CRxRx)i-2CRx(OH)-,
-C(0)(CRxRx)o-iO- -C(0)(CRxRx)i-2NHS(0)2-, -C(0)NRx(CRxRx)i-2- or -S(0)2(CRxRx)o-2-;
A is adamantanyl, azepanyl, azetidinyl, C3-6 cycloalkyl, diazepanyl, dihydroinonyl,
dihydropyrimidinonyl, dioxidoisothiazolidinyl, dioxidothiazinanyl,
dioxotetrahydrothiophenyl, dioxotetrahydrothiopyranyl, dioxothiomo holinyl, furanyl, imidazolyl, imidazolidinonyl, indolyl, isoquinolinyl, isoxazolyl, morpholinyl, mo holinonyl, naphthalenyl, oxazolidinonyl, oxadiazolyl, oxetanyl, oxazolyl, phenyl, piperidinyl, piperidinonyl, piperazinyl, piperazinonyl, pyrazinyl, pyrazolyl, pyrazolidinonyl, pyridazinonyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl, pyrrolyl, quinolinyl, quinolizinonyl, tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, or triazolyl, each substituted with zero, 1, or 2 R3a;
each R3a is independently F, CI, -OH, -NH2, C1-3 alkyl, C 1-2 fluoroalkyl, or -C(0)NRxRx; each R4 is independently F, -OH, C 1-2 alkyl, or -OCH3; or two R4 attached to the same carbon atom form =0; each R.5 is independently F, CI, -CN, C1-2 alkyl, C1-2 fluoroalkyl, or -OCH3;
each Rx is independently H or -CH3;
Rz is H, Ci-2 alkyl, or C1-2 fluoroalkyl;
m is zero, 1, 2, 3, or 4; and
n is zero, 1, 2, or 3.
odiment provides a compound of Formula (I) or a salt thereof, wherein Y
is
Figure imgf000006_0001
; and Ri, R2, R2a, R3, R4, R5, m, and n are defined in the first aspect.
Compounds of this embodiment have the structure of Formula (la):
Figure imgf000006_0002
Included in this embodiment are compounds in which Ri is -CH(CH3)2.
odiment provides a compound of Formula (I) or a salt thereof, wherein
is
Figure imgf000006_0003
; and Ri, R2, R2a, R3, R4, R5, m, and n are defined in the first aspect.
Compounds of this embodiment have the structure of Formula (lb):
Figure imgf000006_0004
Included in this embodiment are compounds in which Ri is -CH(CH3)2.
odiment provides a compound of Formula (I) or a salt thereof, wherein
is
Figure imgf000006_0005
; and Ri, R2, R2a, R3, R4, R5, m, and n are defined in the first aspect. Compounds of this embodi a (Ic):
Figure imgf000007_0001
(Ic)
Included in this embodiment are compounds in which Ri is -CH(CH3)2.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein Y
is
Figure imgf000007_0002
; and RX R2 R2A R3 R4 R5 ni5 and n are defined in the first aspect. Compounds of this emb a (Id):
Figure imgf000007_0003
(Id).
Included in this embodiment are compounds in which Ri is -CH(CH3)2.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein Y
lS
Figure imgf000007_0004
; and Ri, R2, R2a, R3, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which Y i
Figure imgf000007_0005
Also included in this embodiment are compounds in Ri is -CH(CH3)2.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein Y
is
Figure imgf000007_0006
; and Rl, R2, R2a, R2b, R2c, R3, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which Ri is -CH(CH3)2.
odiment provides a compound of Formula (I) or a salt thereof, wherein Y
is
Figure imgf000008_0001
and Ri, R2, R2a, R2b, R2c, R3, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which R2b is R. Also included in this embodiment are compounds in which R2b is R2a. Additionally, included in this embodiment are compounds in which Ri is -CH(C]¾)2.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein Ri is H, CI, -CN, Ci-4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxy-fluoroalkyl, C3-6 cycloalkyl, -CH2(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), or tetrahydropyranyl; and R2, R2a, R2b, R2c, R3, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which Ri is H, C1-4 alkyl, C1-3 fluoroalkyl, or C3-6 cycloalkyl. Also included in this embodiment are compounds in which Ri is -CH2CH3 or -CH(CH3)2. Additionally, included in this embodiment are compounds in which Ri is -CH(CH3)2.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein
R2 is Ci-4 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-2 aminoalkyl, -(CH2)o-40(Ci-2 alkyl), C3-6 cycloalkyl, -(CH2)i-2C(0)NRxRx, -CH2(C3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl; and Y, Ri, R2a, R2b, R2c, R3, R4, R5, Rx, m, and n are defined in the first aspect. Included in this embodiment are compounds in which R2 is CM alkyl, C1-2 fluoroalkyl, CM hydroxyalkyl, -(CH2)i-30CH3, C3-6 cycloalkyl, -CH2C(0)NRxRx, -CH2(C3-e cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, or phenyl. Also included in this embodiment are compounds in which R2 is -CH3,
-CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2OH, -CH2CH2CH2OH,
-CH2C(CH3)20H, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2(cyclopropyl),
-CH2(phenyl), -CH2C(0)NH2, tetrahydrofuranyl, or phenyl.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein Ri is -CH(CH3)2; R2 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)20H, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2(cyclopropyl), -CH2(phenyl), -CH2C(0)NH2, tetrahydrofuranyl, or phenyl; and R.2b, R2c, R3, R4, R5, Rx, m, and n are defined in the first aspect. Included in this
embodiment are compounds in which Y is
Figure imgf000009_0001
One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R2a is independently H, F, CI, -CN, -NRXRX, Ci-6 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkoxy, -(CH2)o-20(C i-3 alkyl), -(CH2)o-3C(0)NRxRx,
-(CH2)i-3(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), -C(0)NRx(C i-3 alkyl), -CRX=CRXRX, -CRx=CH(C3-6 cycloalkyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry; and Y, Ri, R2, R2t>, R2c, R3, R4, R5, Rx, Ry, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each R2a is independently H, F, CI, -CN, -NRxRx, C i-6 alkyl, C1-2 fluoroalkyl, C1-3 hydroxyalkyl, -(CH2)o-20(Ci-2 alkyl), -(CH2)o-2C(0)NRxRx, -(CH2)i-3(cyclopropyl), -C(0)0(Ci-2 alkyl), -C(0)NRx(Ci-3 alkyl), -CRX=CH2,
Figure imgf000009_0002
cycloalkyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry. Also included in this embodiment are compounds in which each R2a is independently H, F, CI, -CN, -NH2, C 1-5 alkyl, -CF3, -CH2OH, -OCH3, -CH2OCH3, -CH2CH2(cyclopropyl), -C(0)OCH3, -C(0)N(CH3)2, -C(0)NH(CH2CH2CH3),
-CH=CH2, -C(CH3)=CH2, -CH=CH(cyclopropyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R2a is independently H, F, CI, -CN, -NRXRX, Ci-6 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkoxy, -(CH2)o-20(C i-3 alkyl), -(CH2)o-3C(0)NRxRx,
-(CH2)i-3(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), -C(0)NRx(C i-3 alkyl), -CRx=CRxRx, -CRx=CH(C3-6 cycloalkyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, or 2 Ry; each Ry is independently F, CI, -CN, C1-2 alkyl, C1-2 alkoxy, -NRxC(0)(C i-2 alkyl), -C(0)NRxRx, C3-6 cycloalkyl, or morpholinyl; and Y, Ri, R2, R2b, R2c, R3, R4, R5, Rx, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each R2a is independently H, F, CI, -CN, -NRXRX, Ci-6 alkyl, C 1-2 fluoroalkyl, Ci-3 hydroxyalkyl, -(CH2)o-20(Ci-2 alkyl), -(CH2)o-2C(0)NRxRx, -(CH2)i-3(cyclopropyl), -C(0)0(Ci-2 alkyl), -C(0)NRx(Ci-3 alkyl), -CRX=CH2,
Figure imgf000010_0001
cycloalkyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1 , or 2 Ry; and each Ry is independently F, -CN, -CH3, -CF3, -OCH3, -NHC(0)CH3, -C(0)NH2,
-C(0)NH(CH3), cyclopropyl, or morpholinyl. Also included in this embodiment are compounds in which each R2a is independently H, F, CI, -CN, -NH2, C1-5 alkyl, -CF3, -CH2OH, -OCH3, -CH2OCH3, -CH2CH2(cyclopropyl), -C(0)OCH3, -C(0)N(CH3)2, -C(0)NH(CH2CH2CH3), -CH=CH2, -C(CH3)=CH2, -CH=CH(cyclopropyl),
-C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1 , or 2 Ry; and each Ry is independently F, -CN, -CH3, -CF3, -OCH3, -NHC(0)CH3, -C(0)NH2,
-C(0)NH(CH3), cyclopropyl, or morpholinyl.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is -Li-A; and Y, Ri, R2, R2a, R2t>, R2c, R4, R5, Li, A, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each Li is a bond,
-(CRxRx)i-2- -(CRxRx)i-20- -CRxRxC(0)-, -(CRxRx)2NRx(CRxRx)o-i-
-CRxRxC(0)NRx(CRxRx)o-4-, -C(0)(CRxRx)o-3- -C(0)(CRxRx)o-2NRx(CRxRx)o-2-, -C(0)(CRxRx)i-2C(0)NRx-, -C(0)(CRxRx)o-iO-, -C(0)(CRxRx)i-2NHS(0)2-,
-C(0)NRx(CRxRx)i-2-, or -S(0)2(CRxRx)o-2-. Also included in this embodiment are compounds in which Li is a bond, -(CRxRx)i-2-, -CRxRxC(0)-, -C(0)(CRxRx)o-i- -C(0)0- or -S(0)2(CRxRx)o-2-
One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is -Li-A; Li is a bond, -(CRxRx)i-2- -CRxRxC(0)-, -C(0)(CRxRx)o-i- -C(0)0- or -S(0)2(CRxRx)o-2-; A is azetidinyl, C3-6 cycloalkyl, dioxotetrahydrothiophenyl, oxetanyl, phenyl, piperidinyl,, pyrazolyl, pyrazolidinonyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, or triazolyl, each substituted with zero, 1, or 2 R.3a; and Y, Ri, R2, R2a, R2b, R2c, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which Ri is
- Also included in this embodiment are compounds in which Y is
Figure imgf000011_0001
One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is -CH2(methyl triazolyl), -CH2(trifluoromethyl phenyl), -CH2(difluoromethyl, fluorophenyl), -CH2(fluoro, chlorophenyl), -CH2(difluorocyclopropyl),
-CH2CH2(pyrrolidin-dionyl), -CH2(oxetanyl), -CH2(tetrahydropyranyl),
-CH2C(0)(hydroxypyrrolidinyl), -CH2C(0)(pyrazolidinonyl), -CH2C(0)(pyrrolidinyl), -CH2(dimethyl pyrazolyl), -CH2(methyl pyrazolyl), -CH2(pyrazolyl),
-CH2(cyclopropyl), -CH2(tetrahydrofuranyl), -CH2(/'-propyl pyrazolyl), -CH2(«-propyl pyrazolyl), -CH(CH3)(methyl pyrazolyl), -C(0)(aminocyclopropyl),
-C(0)(hydroxypyrrolidinyl), -C(0)(methyl, hydroxypyrrolidinyl),
-C(0)CH2(pyrrolidinonyl), -C(0)CH2(pyrrolidinyl), -C(0)0(methyl pyrrolidinyl), -S(0)2CH2CH2(pyrrolidinyl), -CH2(hydroxytetrahydropyranyl), or a cyclic group selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinonyl,
tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, piperidinyl, and
dioxotetrahydrothiophenyl, each substituted with zero, 1, or 2 R3a; and Y, Ri, R2, R2a, R2b, R2c, R3a, R4, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each
One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is H, Ci-6 alkyl, Ci-6 fluoroalkyl, Ci-6 hydroxyalkyl, C 1-3 cyanoalkyl, -(CH2)o-40(Ci-3 alkyl), -(CH2CH20)2-30(Ci-3 alkyl), -CH2CH2NRXRX, -CRxRxC(0)OH,
-(CRxRx)o-2C(0)NRxRx, -CH2C(0)NRx(Ci-3 alkyl), -CH2C(0)NRx(Ci-4 hydroxyalkyl), -(CRxRx)o-2S(0)2(Ci-3 alkyl), -C(0)(Ci-3 alkyl), -C(0)(Ci-3 fluoroalkyl),
-C(0)CRxRxNRxRx, -C(0)(Ci-6 hydroxyalkyl), or -NRxC(0)(Ci-3 alkyl); and Ri, R2, R2a, R2b, R2c, R4, R5, Rx, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each R3a is independently F, CI, -OH, -NH2, C1-3 alkyl, C1-2 fluoroalkyl, or -C(0)NRxRx. Also included are compounds in which each R3a is independently F, -OH, -CH3, -CH(CH3)2, -CF3, or -C(0)NH2.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R4 is independently F, -OH, -CH3, or -OCH3; or two R4 attached to the same carbon atom form =0; and Ri, R2, R2a, R2t>, R2c, R3, R5, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each R4 is independently F, -CH3, or -OCH3; or two R4 attached to the same carbon atom form =0.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R5 is independently F, -CN, -CH3, -CF3, or -OCH3; and Ri, R2, R2a, R2t>, R2c, R3, R4, m, and n are defined in the first aspect. Included in this embodiment are compounds in which each R5 is independently F, -CH3, or -CF3. Also included in this embodiment are compounds in which R5 is F and n is zero or 1.
provides a compound of Formula (I) or a salt thereof, wherein Y
Figure imgf000012_0001
CH(CH3)2; R5 is F; m is zero; n is zero or 1; and R2, R2a, R3, and
R4 are defined in the first aspect. Included in this embodiment are compounds in which is zero.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein
Ri is H, Ci-4 alkyl or C1-3 fluoroalkyl, or C3-6 cycloalkyl; R2 is C1-4 alkyl, C1-2 fluoroalkyl, CM hydroxyalkyl, -(CH2)i-30CH3, C3-6 cycloalkyl, -CH2C(0)NRxRx, -CH2(C3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, or phenyl; each R2a is independently H, F, CI, -CN, -NRxRx, Ci-6 alkyl, C1-2 fluoroalkyl, C1-3 hydroxyalkyl, -(CH2)o-20(Ci-2 alkyl), -(CH2)o-2C(0)NRxRx, -(CH2)i-3(cyclopropyl), -C(0)0(Ci-2 alkyl), -C(0)NRx(Ci-3 alkyl),
Figure imgf000012_0002
cycloalkyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry; each Ry is independently F, CI, -CN, C1-2 alkyl, C1-2 alkoxy, -NRxC(0)(Ci-2 alkyl), -C(0)NRxRx, C3-6 cycloalkyl, or morpholinyl; R3 is (a) -Li-A; or (b) H, Ci-6 alkyl, Ci-6 fluoroalkyl, Ci-6 hydroxyalkyl, C1-3 cyanoalkyl, -(CH2)o-30(Ci-2 alkyl), -(CH2CH20)2-30(Ci-2 alkyl), -CH2CH2NRXRX, -CRxRxC(0)OH, -(CRxRx)o-2C(0)NRxRx, -CH2C(0)NRx(Ci-2 alkyl), -CH2C(0)NH(Ci-4 hydroxyalkyl), -(CRxRx)i-2S(0)2(Ci-2 alkyl), -C(0)(Ci-2 alkyl), -C(0)(Ci-2 fluoroalkyl),
-C(0)CRxRxNRxRx, -C(0)(Ci-4 hydroxyalkyl), or -NRxC(0)(Ci-2 alkyl); Li is a bond, -(CRxRx)i-2- -CRxRxC(0)-, -C(0)(CRxRx)o-i-, -C(0)0- or -S(0)2(CRxRx)o-2-; A is azetidinyl, C3-6 cycloalkyl, dioxotetrahydrothiophenyl, oxetanyl, phenyl, piperidinyl,, pyrazolyl, pyrazolidinonyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, or triazolyl, each substituted with zero, 1, or 2 R3a; each R3a is independently F, CI, -OH, -NH2, C1-3 alkyl, Ci-2 fluoroalkyl, or -C(0)NRxRx; each R4 is independently F, -OH, -CH3, or -OCH3; or two R4 attached to the same carbon atom form =0; each R5 is independently F, -CN, -CH3, -CF3, or -OCH3; and Rz is H or -CH3.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein Ri is -CH2CH3 or -CH(CH3)2; R2 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)2OH, -CH2CHF2, -CH2CF3,
-CH2CH2OCH3, -CH2(cyclopropyl), -CH2(phenyl), -CH2C(0)NH2, tetrahydrofuranyl, or phenyl; each R2a is independently H, F, CI, -CN, -NH2, C1-5 alkyl, -CF3, -CH2OH, -OCH3, -CH2OCH3, -CH2CH2(cyclopropyl), -C(0)OCH3, -C(0)N(CH3)2,
-C(0)NH(CH2CH2CH3), -CH=CH2, -C(CH3)=CH2, -CH=CH(cyclopropyl),
-C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry; each Ry is
independently F, -CN, -CH3, -CF3, -OCH3, -NHC(0)CH3, -C(0)NH2,
-C(0)NH(CH3), cyclopropyl, or mo holinyl; Ra> is R2 or R2a; R2c is R2 or R2a; provided that one of Ra> and R2c is R2, and the other of Ra> and R2c is R2a; R3 is H, -CH3,
-CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2CF3, -CH2CH2CH2CF3, -CH2CH2CH(CF3)2, -CH2CH2OH, -CH2CH2CH2OH, -C(CH3)2OH, -CH2C(CH3)2OH, -CH2CH2C(CH3)2OH, -CH2CH(OH)CH(CH3)2, -CH2CH(OH)CH2OH, -CH(CH2CH2OH)2, -CH2CN, -CH2CH2CN, -CH2CH2OCH3, -CH2CH2CH2OCH3, - (CH2CH20)2-30CH3, -CH2CH2NH(CH3), -C(CH3)2C(0)OH, -CH2C(0)NH2, -CH2C(0)NH(CH3), -CH2C(0)N(CH3)2, -CH2C(0)NH(CH2CH3), -CH2C(0)NH(CH2CH(CH3)OH), -CH2C(0)NH(CH2C(CH3)2OH), -CH(CH3)C(0)NH2, -C(CH3)2C(0)NH2, -CH2CH2C(0)NH2, -CH2CH2S(0)2CH3, -C(0)CH3, -C(0)CF3, -C(0)CH2N(CH3)2, -C(0)C(CH3)2NH2, -C(0)CH(CH3)NH(CH3),
-C(0)C(CH3)2NH(CH3), -C(0)CH2CH(CH3)OH, -C(0)CH2C(CH3)2OH,
-C(0)C(CH3)2CH2OH, -NHC(0)CH3, -CH2(methyl triazolyl), -CH2(trifluoromethyl phenyl), -CH2(difluoromethyl, fluorophenyl), -CH2(fluoro, chlorophenyl),
-CH2(difluorocyclopropyl), -CH2CH2(pyrrolidin-dionyl), -CH2(oxetanyl),
-CH2(tetrahydropyranyl), -CH2C(0)(hydroxypyrrolidinyl), -CH2C(0)(pyrazolidinonyl), -CH2C(0)(pyrrolidinyl), -CH2(dimethyl pyrazolyl), -CH2(methyl pyrazolyl),
-CH2(pyrazolyl), -CH2(cyclopropyl), -CH2(tetrahydrofuranyl), -CH2(z-propyl pyrazolyl), -CH2(«-propyl pyrazolyl), -CH(CH3)(methyl pyrazolyl),
-C(0)(aminocyclopropyl), -C(0)(hydroxypyrrolidinyl), -C(0)(methyl,
hydroxypyrrolidinyl), -C(0)CH2(pyrrolidinonyl), -C(0)CH2(pyrrolidinyl),
-C(0)0(methyl pyrrolidinyl), -S(0)2CH2CH2(pyrrolidinyl),
-CH2(hydroxytetrahydropyranyl), or a cyclic group selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, piperidinyl, and dioxotetrahydrothiophenyl, each substituted with zero, 1, or 2 R3a; each R3a is independently F, -OH, -CH3, -CH(CH3)2, -CF3, or -C(0)NH2; R5 is F; m is zero; and n is zero or 1.
One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is selected from 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methylpyridin-2(lH)-on (1); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (2); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3,6- trimethylpyridin-2(lH)-one (3);5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,6- dimethylpyridin-2(lH)-one (6); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,4- dimethylpyridin-2(lH)-one (8); 3-amino-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l-methylpyridin-2(lH)-one (9); 3-fluoro-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol- 2-yl)-l-methylpyridin-2(lH)-one (13); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)- l,3,4-trimethylpyridin-2(lH)-one (14); l-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-3-methylpyridin-2(lH)-one (15); l-isopropyl-5-(3-isopropyl-5-(piperidin-4- yl)-lH-indol-2-yl)pyridin-2(lH)-one (16); 3-amino-5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (19); 5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-3-methoxy-l-methylpyridin-2(lH)-one (20); 3-chloro-5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (22); 5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (23); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethyl-2-oxo-l,2- dihydropyridine-3-carbonitrile (24); 3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l,6-dimethylpyridin-2(lH)-one (25); l-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-3,4-dimethylpyridin-2(lH)-one (26); 5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-3-methoxy-l,6-dimethylpyridin-2(lH)-one (28); 5-(3-isopropyl-5-(piperidin- 4-yl)-lH-indol-2-yl)-3-methoxy-l,4-dimethylpyridin-2(lH)-one (29); l-(2- hydroxyethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)- one (30); 3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (31); 3-chloro-l-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl) pyridin-2(lH)-one (32); 3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,6- dimethylpyridin-2(lH)-one (33); l-(cyclopropylmethyl)-5-(3-isopropyl-5-(piperidin-4- yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (34); l,3-diethyl-5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-6-methylpyridin-2(lH)-one (35); l-isobutyl-5-(3- isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (36); methyl 5- (3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridine-3- carboxylate (37); l-(3-hydroxypropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)- 3 -methy lpy ridin-2( 1 H)-one (38); 5-(3-isopropy 1-5 -(piperidin-4-yl)- 1 H-indol-2-y 1)- 1 -(2- methoxyethyl)-3-methylpyridin-2(lH)-one (39); l-(2,2-difluoroethyl)-5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (40); 5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(trifluoromethyl)pyridin-2(lH)-one (41); 5- (3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methyl-l-(tetrahydrofuran-3-yl)pyridin- 2(lH)-one (42); l-(2-hydroxy-2-methylpropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-3-methylpyridin-2(lH)-one (43); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol- 2-yl)-3-methyl-l-phenylpyridin-2(lH)-one (44); 5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-3-methyl-l-(2,2,2-trifluoroethyl)pyridin-2(lH)-one (45); l-benzyl-5-(3- isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (46); 5-(3- isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridine-3- carbonitrile (47); l-(2-hydroxy-2-methylpropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)pyridin-2(lH)-one (48); 2-(5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2- oxopyridin-l(2H)-yl)acetamide (49); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methyl-[3,3'-bipyridin]-2(lH)-one (50); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)- l-methyl-3-(prop-l-en-2-yl)pyridin-2(lH)-one (51); (E)-3-(2-cyclopropylvinyl)-5-(3- isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (52); 5-(3- isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-phenylpyridin-2(lH)-one (53); 5- (3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin- 2(lH)-one (54); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(p-tolyl) py ridin-2( lH)-one (55); 3 -(5 -(3 -isopropy l-5-(piperidin-4-y 1)- 1 H-indol-2-y 1)- 1 -methy 1-2- oxo-1, 2-dihydropyridin-3-yl)benzonitrile (56); 5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-2'-methoxy-l-methyl-[3,3'-bipyridin]-2(lH)-one (57); 3-(5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)benzamide (58); 3-(5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridin- 3-yl)-N-methylbenzamide (59); N-(3-(5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methyl-2-oxo-l,2-dihydropyridin-3-yl)phenyl)acetamide (60); 3-(3,3-dimethylbut l)-5- (3-isopropy 1-5 -(piperidin-4-y 1)- 1 H-indol-2-y 1)- 1 -methy lpy ridin-2(l H)-one (61 ); 3-(2- cyclopropylethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin- 2(lH)-one (62); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-N,N,l-trimethyl-2-oxo-
1.2- dihydropyridine-3-carboxamide (63); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l-methyl-2-oxo-N-propyl-l,2-dihydropyridine-3-carboxamide (64); 5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethyl-[3,3'-bipyridin]-2(lH)-one (65); 3- isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one
(66) ; 3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one
(67) ; l,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)pyridin-2(lH)-one (68); -(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrrolidine-l-carbonyl) pyridin-2(lH)-one (69); 3-(hydroxymethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l-methylpyridin-2(lH)-one (70); 2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl) piperidin-l-yl)-N,N-dimethylacetamide (71); 5-(3- isopropyl-5-(l-((l-methyl-lH-l,2,4-triazol-3-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-
1.3- dimethylpyridin-2(lH)-one (72); 5-(5-(l-(3-hydroxy-3-methylbutyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,3,4-trimethylpyridin-2(lH)-one (73); 5-(5-(l-(3-hydroxy-3- methylbut l)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)-one (74); 5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin- 2(lH)-one (75); 3-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH- indol-5-yl)piperidin-l-yl)propanenitrile (76); 5-(3-isopropyl-5-(l-(4-(trifluoromethoxy) benzyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (77); 5-(5-(l-(5- (difluoromethoxy)-2-fluorobenzyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (78); 5-(3-isopropyl-5-(l-(4,4,4-trifluorobutyl)piperidin-4-yl)- 1 H-indol-2-y 1)- 1 ,3 -dimethy lpyridin-2(l H)-one (79); 5 -(5-( 1 -(5 -chloro-2- fluorobenzyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (80); 5-(5-(l-(l,l-dioxidotetrahydrothiophen-3-yl)piperidin-4-yl)-3-isopropyl-lH-indol- 2-yl)-l,3-dimethylpyridin-2(lH)-one (81); 3-(4-(2-(l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)propanamide (82); 5-(5- (l-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (83); l-(2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)ethyl)pyrrolidine-2,5-dione (84); 5-(5-(l-(3- hydroxypropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)- one (85); 5-(5-(l-isopentylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (86); 5-(5-(l-cyclohexylpiperidin-4-yl)-3-isopropyl-lH-indol-
2- yl)-l,3-dimethylpyridin-2(lH)-one (87); 5-(3-isopropyl-5-(l-(4,4,4-trifluoro-3- (trifluoromethyl)butyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (88); 5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-methyl-3- phenylpyridin-2(lH)-one (89); 5-(5-(l-isopentylpiperidin-4-yl)-3-isopropyl-lH-indol-2- yl)-l-methyl-3-phenylpyridin-2(lH)-one (90); 3-chloro-5-(5-(l-isopentylpiperidin-4-yl)-
3- isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (91); 3-chloro-5-(3-isopropyl- 5-(l-(oxetan-3-ylmethyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (92); 3-chloro-5-(3-isopropyl-5-(l-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)- lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (93); 5-(3-isopropyl-5-(l-(oxetan-3- ylmethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (94); 3-chloro-5-(3-isopropyl-5-(l-(2-methoxyethyl)piperidin-4-yl)-lH-indol-2-yl)-l,4- dimethylpyridin-2(lH)-one (95); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)acetonitrile (96); 3-chloro- 5-(5-(l-cyclopentylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (97); 3-chloro-5-(3-isopropyl-5-(l-(2-(2-(2-methoxyethoxy)ethoxy)ethyl) piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (98); 3-chloro-5-(3- isopropyl-5-(l-(3-methoxypropyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (99); 5-(3-isopropyl-5-(l-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)- lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (100); 3-chloro-5-(3- isopropyl-5-(l-(2-(2-methoxyethoxy)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l,4- dimethylpyridin-2(lH)-one (101); 3-chloro-5-(3-isopropyl-5-(l-(3,3,3-trifluoropropyl) piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (102); 5-(3-isopropyl-5-(l- (2-methoxyethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin- 2(lH)-one (103); 5-(3-isopropyl-5-(l-(4,4,4-trifluorobutyl)piperidin-4-yl)-lH-indol-2-yl)- l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (104); 3-chloro-5-(3-isopropyl-5-(l- (4,4,4-trifluorobutyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (105); 3-chloro-5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (106); 3-chloro-5-(3-isopropyl-5-(l-(2-(methylsulfonyl)ethyl) piperidin-4-yl)- lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (107); 5-(3-isopropyl-5-(l-(2- (methylsulfonyl)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl) pyridin-2(lH)-one (108); 5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-(2- methoxyethyl)-3-methylpyridin-2(lH)-one (109); l-isobutyl-5-(3-isopropyl-5-(l-(4,4,4- trifluorobutyl)piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (110); 1-benzyl- 5-(3-isopropyl-5-(l-(4,4,4-trifluorobutyl)piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin- 2(lH)-one (111); l-isobutyl-5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3- methylpyridin-2(lH)-one (112); l-benzyl-5-(5-(l-isobut lpiperidin-4-yl)-3-isopropyl-lH- indol-2-yl)-3-methylpyridin-2(lH)-one (113); 2-(4-(3-isopropyl-2-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (114); 2-(4- (2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l- yl)-N-methylacetamide (117); (S)-5-(5-(l-(2-(3-hydroxypyrrolidin-l-yl)-2- oxoethyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (119); (R)-5-(5-(l-(2-(3-hydroxypyrrolidin-l-yl)-2-oxoethyl) piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (120); 5-(3-isopropyl-5-(l-(2-oxo-2-(3- oxopyrazolidin-l-yl)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (121); 5-(3 -isopropy l-5-( 1 -(2-oxo-2-(py rrolidin- 1 -y l)ethyl) piperidin-4-y 1)- lH-indol-2- yl)-l,3-dimethylpyridin-2(lH)-one (122); (R)-5-(3-isopropyl-5-(l-(2-oxopyrrolidin-3- yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (123); 2-(4-(2-(l,5- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl) piperidin-l-yl)-N- (2-hydroxy-2-methylpropyl)acetamide (124); (R)-2-(4-(2-(l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-(2- hydroxypropyl)acetamide (125); (S)-2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-(2-hydroxypropyl)acetamide (126); 5-(3- isopropyl-5-(l-(l-methyl-2-oxopyrrolidin-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (127); 2-(4-(3-isopropyl-2-(5-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (128); 2-(4- (3-isopropyl-2-(5-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl) piperidin-l-yl)-N-methylacetamide (129); 2-(4-(2-(l-ethyl-5-methyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (132); 2-(4-(2-(l-ethyl-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5- yl)piperidin-l-yl)-N,N-dimethylacetamide (133); 2-(4-(3 -isopropyl-2-( 1,4,5 -trimethy 1-6- oxo-1, 6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (134); 2-(4-(3-isopropyl-2-(l,4,5-trimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5- yl)piperidin-l-yl)-N-methylacetamide (135); 2-(4-(2-(l-ethyl-4,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (136); 2-(4-(2-(l-ethyl-4,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH- indol-5-yl)piperidin-l-yl)-N-methylacetamide (137); 2-(4-(3-isopropyl-2-(l,2,5- trimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N- dimethylacetamide (138); 2-(4-(3-isopropyl-2-(l,2,5-trimethyl-6-oxo-l,6-dihydropyridin- 3-yl)-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (139); 2-(4-(3-isopropyl-2-(5- methoxy-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N- methylacetamide (140); 2-(4-(3-isopropyl-2-(5-methoxy-l,4-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (141); 2-(4- (3-isopropyl-2-(5-methoxy-l,2-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5- yl)piperidin-l-yl)-N-methylacetamide (142); 2-(4-(3-isopropyl-2-(5-methoxy-l,2- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N- dimethylacetamide (143); 2-(4-(2-(5-cyano-l,2-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (144); 2-(4-(2-(5-cyano- l,2-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)- N,N-dimethylacetamide (145); 2-(4-(2-(5-cyano-l,4-dimethyl-6-oxo-l,6-dihydropyridin- 3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (146); 2-(4-(2-(5- cyano-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin- l-yl)-N,N-dimethylacetamide (147); 2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-2-methylpropanoic acid (148); 5-(3- isopropyl-5-(l-(5-methyl-2-oxotetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (149); 2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)acetamide (150); 2-(4-(2-(l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-2-methylpropanamide (151); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH- indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (152); 2-(4-(2-(5-chloro-l,4-dimethyl- 6-oxo-l, 6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N- methylacetamide (153); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-2-methylpropanamide (154); 2-(4-(2-(5-chloro- l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)- N-ethylacetamide (155); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-
3- isopropyl-lH-indol-5-yl)piperidin-l-yl)propanamide (156); 2-(4-(2-(5-chloro-l,4- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-ethyl-lH-indol-5-yl) piperidin-l-yl)-N,N- dimethylacetamide (157); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-
4- fluoro-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (158); 2-(4- (3-isopropyl-2-(l-(2-methoxyethyl)-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-
5- yl)piperidin-l-yl)-N,N-dimethylacetamide (159); 2-(4-(3-isopropyl-2-(l-(2- methoxyethyl)-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)- N-methylacetamide (160); 2-(4-(2-(l-isobutyl-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (161); 2-(4-(2-(l-benzyl-5- methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N- methylacetamide (162); 2-(4-(2-(l-isobutyl-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (163); 2-(4-(2-(l- benzyl-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l- yl)-N,N-dimethylacetamide (164); 2-(4-(3 -isopropyl-2-(5-methyl-6-oxo-l -(2,2,2- trifluoroethy 1)- 1 ,6-dihy dropy ridin-3 -y 1)- lH-indol-5 -y l)piperidin- 1 -y 1)-N,N- dimethylacetamide (165); 2-(4-(2-(l-(2,2-difluoroethyl)-5-methyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (166); 2-(4-(2-(l-(2 -hydroxy ethyl)-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl- lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (167); 2-(4-(2-(5-ethyl-l-methyl- 6-oxo-l, 6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N- dimethylacetamide (168); 2-(4-(3-isopropyl-2-(l-methyl-2-oxo-l,2-dihydro-[3,3'- bipyridin]-5-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (169); 2-(4-(3- isopropyl-2-(l-methyl-6-oxo-5-phenyl-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-
1- yl)-N,N-dimethylacetamide (170); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (171); 5-(3-isopropyl-5-(l-(2- (methylamino)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (172); 5- (3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(piperidin-l-yl) pyridin-2(lH)-one (173); 5-(5-(l-(l-acetylazetidin-3-yl)piperidin-4-yl)-3-isopropyl-lH- indol-2-yl)-3-chloro-l,4-dimethylpyridin-2(lH)-one (174); 5-(3-isopropyl-5-(l-(oxetan- 3-yl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (175); 5-(3-isopropyl-5- (l-(2-(methylamino)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (176); 5-(3-isopropyl-5-(l-(tetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l- methylpyridin-2(lH)-one (177); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl) piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (178); 5-(3-isopropyl-5-(l- (oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (179); 5-(3- isopropyl-5-(l-(tetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin- 2(lH)-one (180); 5-(3-isopropyl-5-(l-methylpiperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (181); 5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-
2- yl)-l,3-dimethylpyridin-2(lH)-one (182); 5-(3-isopropyl-5-(l-((l-methyl-lH-pyrazol-
3- yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (195); 5-(3- isopropyl-5-(l-((l-methyl-lH-pyrazol-4-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (196); 5-(3-isopropyl-5-(l-((l-methyl-lH-pyrazol-5-yl) methyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (197); 5-(3- isopropyl-5-(l-((l-methyl-lH-l,2,4-triazol-5-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)- l,3-dimethylpyridin-2(lH)-one (198); 5-(5-(l-(4,4-difluorocyclohexyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (199); 5-(5-(l-((4H-pyrazol-3- yl)methyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (200); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3- methoxy-l-methylpyridin-2(lH)-one (201); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4- yl)-lH-indol-2-yl)-3-methoxy-l-methylpyridin-2(lH)-one (202); l-ethyl-5-(3-isopropyl- 5-(l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (204); 5-(3- isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3,4- trimethylpyridin-2(lH)-one (206); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-l,3,4-trimethylpyridin-2(lH)-one (207); l-ethyl-5-(3-isopropyl-5-(l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3,4-dimethylpyridin-2(lH)-one (208); l-ethyl-5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-3,4- dimethylpyridin-2(lH)-one (209); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl) piperidin-4-yl)-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)-one (210); 5-(3-isopropyl-5- (l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)-one (211); 5- (3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,3,4-trimethylpyridin-2(lH)- one (212); l-ethyl-5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-3,4- dimethylpyridin-2(lH)-one (213); 5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol- 2-yl)-l,3,6-trimethylpyridin-2(lH)-one (214); 5-(3-isopropyl-5-(l-(oxetan-3-yl) piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l,4-dimethylpyridin-2(lH)-one (215); 5-(3- isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l,4- dimethylpyridin-2(lH)-one (216); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-3-methoxy-l,6-dimethylpyridin-2(lH)-one (217); 5-(3-isopropyl-5-(l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l,6- dimethylpyridin-2(lH)-one (218); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-l,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (219); 5-(3-isopropyl- 5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l,6-dimethyl-2-oxo-l,2- dihydropyridine-3-carbonitrile (220); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)- lH-indol-2-yl)-l,4-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (221); 5-(3- isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethyl-2- oxo-1, 2-dihydropyridine-3-carbonitrile (222); 5-(5-(l-(cyclopropylmethyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (223); 5-(3-isopropyl-5- (l-propylpiperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (224); 5-(3- isopropyl-5-(l-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (225); 3-chloro-5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4- yl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (226); 3-chloro-5-(3- isopropyl-5-(l-((l-isopropyl-lH-pyrazol-4-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l- methylpyridin-2(lH)-one (227); 5-(3-isopropyl-5-(l-((l-propyl-lH-pyrazol-4-yl)methyl) piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (228); N-(4-(4-(2-(l,5- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl) cyclohexyl)acetamide (229); 5-(3-isopropyl-5-(l-(4-(trifluoromethyl)cyclohexyl) piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (230); 5-(3-isopropyl-5-(l- (4-(trifluoromethyl)cyclohexyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin- 2(lH)-one (231); 5-(5-(l-((l,3-dimethyl-lH-pyrazol-4-yl)methyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (232); 5-(3-isopropyl-5-(l-(4- isopropylcyclohexyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (233); 5-(3-isopropyl-5-(l-(4-isopropylcyclohexyl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpy ridin-2(l H)-one (234); 5 -(3 -isopropy 1-5 -( 1 -isopropy lpiperidin-4-y 1)- 1 H-indol-
2- yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (235); 5-(5-(l-(2-hydroxyethyl)piperidin-4-yl)-
3- isopropyl-lH-indol-2-yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (236); 5-(3-isopropyl-5- (l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,4-dimethyl-[3,3'-bipyridin]-2(lH)-one (237); 3-chloro-5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,4- dimethylpyridin-2(lH)-one (238); 3-chloro-5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4- y l)piperidin-4-y 1)- 1 H-indol-2-y 1)- 1 ,4-dimethy lpy ridin-2(l H)-one (241 ); 3 -chloro-5 -(3 - isopropyl-5-(l-methylpiperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (240); 5-(5-(l-acetylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-chloro-l,4- dimethylpy ridin-2(l H)-one (241 ); 3 -chloro-5 -(3 -isopropy 1-5 -( 1 -propy lpiperidin-4-y 1)- 1 H- indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (242); 3-chloro-5-(5-(l-(l,5-dihydroxypentan- 3-yl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (243); 5- (3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5- yl)pyridin-2(lH)-one (244); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l- methyl-[3,3'-bipyridin]-2(lH)-one (245); 5-(3-isopropyl-5-(l-methylpiperidin-4-yl)-lH- indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (246); 5-(3-isopropyl-5-(l- methylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (247); 3- chloro-5-(3-isopropy 1-5 -( 1 -(oxetan-3 -y l)piperidin-4-y 1)- 1 H-indol-2-y 1)- 1,4- dimethylpy ridin-2(l H)-one (248); 5 -(3 -isopropy 1-5 -( 1 -propy lpiperidin-4-y 1)- 1 H-indol-2- yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (249); 3-chloro-5-(3-isopropyl-5-(l- ((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)- one (250); 5-(5-(l-butylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-chloro-l,4- dimethylpyridin-2(lH)-one (251); 3-chloro-5-(3-isopropyl-5-(l-((tetrahydrofuran-3- yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (252); 3-chloro- 5 -(5 -( 1 -(2,3-dihy droxypropy l)piperidin-4-y l)-3-isopropy 1- 1 H-indol-2-y 1)- 1 ,4- dimethylpyridin-2(lH)-one (253); 3-chloro-5-(3-isopropyl-5-(l-((tetrahydrofuran-3- yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (254-255); 5-(5- (l-isobut lpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5- yl)pyridin-2(lH)-one (256); 5-(3-isopropyl-5-(l-((tetrahydrofuran-3-yl)methyl)piperidin- 4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (257); 5-(4-fluoro-3- isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin- 2(lH)-one (258); 5-(4-fluoro-3-isopropyl-5-(l-((tetrahydrofuran-3-yl)methyl)piperidin-4- yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (259); l-ethyl-5-(3- isopropy l-5-( 1 -propy lpiperidin-4-y 1)- 1 H-indol-2-y l)-3 -(py rimidin-5 -y l)pyridin-2( lH)-one (260); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l- (2-methoxyethyl)-3-methylpyridin-2(lH)-one (261); l-isobutyl-5-(3-isopropyl-5-(l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (262); l-benzyl-5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol- 2-yl)-3-methylpyridin-2(lH)-one (263); l-(2-hydroxyethyl)-5-(3-isopropyl-5-(l- methylpiperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (264); 5-(3-isopropyl-5- (l-methylpiperidin-4-yl)-lH-indol-2-yl)-3-methyl-l-(2,2,2-trifluoroethyl)pyridin-2(lH)- one (265); l-(2,2-difluoroethyl)-5-(3-isopropyl-5-(l-methylpiperidin-4-yl)-lH-indol-2- yl)-3-methylpyridin-2(lH)-one (266); 5-(5-(l-(4-(2-hydroxypropan-2- yl)cyclohexyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (267-268); 5-(3-isopropyl-5-(l-(l-(l-methyl-lH-pyrazol-4-yl)ethyl)piperidin-4-yl)-lH- indol-2-y 1)- 1 ,3 -dimethy lpy ridin-2(l H)-one (269); 5 -(5 -( 1 -(4-(2-hy droxypropan-2- yl)cyclohexyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (270); 5-(5-(l-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (271); 5-(5-(l-(l-aminocyclopropanecarbonyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (272); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,6-dimethyl-2-oxo-l,2- dihydropyridine-3-carbonitrile (273); 5-(5-(l -(dimethylglycyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,4-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (274); 5- (5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-methoxy-l,6- dimethylpyridin-2(lH)-one (275); 5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-3-methoxy-l,4-dimethylpyridin-2(lH)-one (276); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-(methoxymethyl)-l- methylpyridin-2(lH)-one (277); 3-chloro-5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (278); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,6 rimethylpyridin-2(lH)- one (279); 5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,4- trimethylpyridin-2(lH)-one (280); 5-(5-(l-(dimethylglycyl) piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-l-ethyl-3,4-dimethylpyridin-2(lH)-one (281); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-ethyl-3-methylpyridin- 2(lH)-one (282); l-benzyl-5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol- 2-yl)-3-methylpyridin-2(lH)-one (284); 5-(5-(l-(dimethylglycyl) piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l-isobutyl-3-methylpyridin-2(lH)-one (285); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-methoxy-l-methylpyridin- 2(lH)-one (286); 5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l- (2-methoxyethyl)-3-methylpyridin-2(lH)-one (287); 5-(5-(l-((2R,4S)-4- hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (288); 5-(5-(l-((2S,4R)-4-hydroxy-l-methylpyrrolidine-2- carbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (289); 5-(5-(l-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-lH- indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (290); 5-(5-(l-((2S,3S)-3-hydroxypyrrolidine- 2-carbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (291); 5-(5-(l-((2R,4S)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-lH- indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (292); 5-(5-(l-((2S,4R)-4-hydroxypyrrolidine- 2-carbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (293); 5-(5-(l-(2-amino-2-methylpropanoyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)- l,3-dimethylpyridin-2(lH)-one (296); 5-(3-isopropyl-5-(l-(methyl-L-alanyl)piperidin-4- yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (297); 5-(3-isopropyl-5-(l-(2-methyl- 2-(methylamino)propanoyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)- one (298); 5-(3-isopropyl-5-(l-(methyl-D-alanyl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (299); 5-(3-isopropyl-5-(l-(2-(2-oxopyrrolidin-l- yl)acetyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (300); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (301); 3-chloro-5-(3-isopropyl-5-(l-(2,2,2-trifluoroacetyl) piperidin-4-yl)-lH-indol-2-yl)- l,4-dimethylpyridin-2(lH)-one (302); 5-(5-(l-(3-hydroxy-3-methylbutanoyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (303); 5-(5-(l-(3-hydroxy- 2,2-dimethylpropanoyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin- 2(lH)-one (304); (S)-5-(5-(l-(3-hydroxybutanoyl) piperidin-4-yl)-3-isopropyl-lH-indol-
2- yl)-l,3-dimethylpyridin-2(lH)-one (305); (R)-5-(3-isopropyl-5-(l-(2-(pyrrolidin-2- yl)acetyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (306); (S)-l- methylpyrrolidin-3-yl 4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (307); 3-chloro-5-(3-isopropyl-5-(l- ((2-(pyrrolidin-l-yl)ethyl)sulfonyl) piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (308); 3-chloro-5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (309); 5-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (310); 5-(5-(l-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)piperidin-4-yl)-3-isopropyl- 1 H-indol-2-y 1)- 1 ,3 -dimethy lpyridin-2( 1 H)-one (313); 5 -(5 -( 1 -((3 S,4S)-4- hydroxytetrahydro-2H-pyran-3-yl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (314); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,3,4-trimethylpyridin-2(lH)-one (315); 5-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)- one (316); 5-(5-(l-(2-hydroxy-2-methylpropyl) piperidin-4-yl)-3-isopropyl-lH-indol-2- yl)-3-methoxy-l,4-dimethylpyridin-2(lH)-one (317); 5-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-methoxy-l,6- dimethylpyridin-2(lH)-one (318); 5-(5-(l -((4-hydroxytetrahydro-2H-pyran-4- yl)methyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,4-trimethylpyridin-2(lH)-one (319); 5-(5-(l -((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)-one (320); 5-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,6-dimethyl-2-oxo-l,2- dihydropyridine-3-carbonitrile (321); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-
3- isopropyl-lH-indol-2-yl)-l,4-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (322); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3- (methoxymethyl)-l-methylpyridin-2(lH)-one (323); 5-(5-(l-(2-hydroxy-3-methylbutyl) piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (324); 5-(5-(l- (2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (325); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (326); 3-chloro- 5-(4-fluoro-5-(l-(2 -hydroxy -2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)- l,4-dimethylpyridin-2(lH)-one (327); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l-isobutyl-3-methylpyridin-2(lH)-one (328); l-benzyl-5- (5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3- methylpyridin-2(lH)-one (329); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2- yl)-l-methyl-6'-morpholino-[3,3'-bipyridin]-2(lH)-one (330); 5-(3-isopropyl-5-(l- propylpiperidin-4-yl)-lH-indol-2-yl)-3-(2-methoxypyrimidin-5-yl)-l-methylpyridin- 2(lH)-one (331); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l,5'-dimethyl- [3,3'-bipyridin]-2(lH)-one (332); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2- yl)-l,4-dimethyl-3-(l-methyl-lH-pyrazol-4-yl)pyridin-2(lH)-one (333); 5-(3-isopropyl- 5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(l-methyl-lH-pyrazol-4-yl) pyridin-2(lH)-one (334); N-(5'-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-r- methyl-2'-oxo- ,2'-dihydro-[3,3'-bipyridin]-6-yl)acetamide (335); 5-(3-isopropyl-5-(l- propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,4'-bipyridin]-2(lH)-one (336); 5-(3- isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(2-methylpyrimidin-5- yl)pyridin-2(lH)-one (337); 3-(2-cyclopropylpyrimidin-5-yl)-5-(3-isopropyl-5-(l- propylpiperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (338); 5-(3-isopropyl-5- (l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl) pyridin-2(lH)-one (339); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-3-(3- methoxyphenyl)-l-methylpyridin-2(lH)-one (340); 6'-fluoro-5-(3-isopropyl-5-(l- propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (341); 6'- fluoro-5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,3'- bipyridin]-2(lH)-one (342); 6'-fluoro-5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH- indol-2-yl)-l,5'-dimethyl-[3,3'-bipyridin]-2(lH)-one (343); 5-(3-isopropyl-5-(l- isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,2'-dimethyl-[3,3'-bipyridin]-2(lH)-one (244); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3- (methoxymethyl)-l-methylpyridin-2(lH)-one (345); 5-(3-isopropyl-5-(l-(oxetan-3-yl) piperidin-4-yl)-lH-indol-2-yl)-3-(methoxymethyl)-l-methylpyridin-2(lH)-one (346); 5- (3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-3-(methoxymethyl)-l- methylpyridin-2(lH)-one (347); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2- yl)-3-(methoxymethyl)-l-methylpyridin-2(lH)-one (348); 5-(3-isopropyl-5-(l-(2- methoxyethyl)piperidin-4-yl)-lH-indol-2-yl)-l,6'-dimethyl-[3,3'-bipyridin]-2(lH)-one (349); 5-(3-isopropyl-5-(l-(2-methoxyethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3- (l-methyl-lH-pyrazol-4-yl)pyridin-2(lH)-one (350); 2-(4-(3-isopropyl-2-(5- (methoxymethyl)-l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l- yl)-N,N-dimethylacetamide (351); 2-(4-(3-isopropyl-2-(l-methyl-6-oxo-5-vinyl-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (352); and 5- (3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-(methoxymethyl)-l-methylpyridin- 2(lH)-one (353).
One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is selected from 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methylpyrazin-2(lH)-one (4); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyrazin-2(lH)-one (12); 2-(4-(2-(4,6-dimethyl-5-oxo-4,5-dihydropyrazin-2-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (115); 5-(3-isopropyl- 5-(l-methylpiperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (183); 5-(3- isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (184); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyrazin-2(lH)-one (185); 5-(3-isopropyl-5-(l-(oxetan-3-yl) piperidin-4-yl)-lH- indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (186); 5-(3-isopropyl-5-(l-(tetrahydro-2H- pyran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (187); 5-(3- isopropyl-5-(l-(tetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin- 2(lH)-one (190); 5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyrazin-2(lH)-one (295); and 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (312).
One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is selected from 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2- methylpyridazin-3(2H)-one (5); 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2,5- dimethylpyridazin-3(2H)-one (10); 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2,4- dimethylpyridazin-3(2H)-one (11); 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)- 2,4,5-trimethylpyridazin-3(2H)-one (17); 2-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-4-methylpyridazin-3(2H)-one (18); 2-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)- lH-indol-2-yl)-4,5-dimethylpyridazin-3(2H)-one (27); 2-(4-(2-(l ,5-dimethyl-6-oxo-l,6- dihydropyridazin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N- dimethylacetamide (1 16); 2-(4-(2-(l ,5-dimethyl-6-oxo-l,6-dihydropyridazin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (118); 2-(4-(3-isopropyl-2- ( 1 ,4,5 -trimethy 1-6-oxo- 1 ,6-dihy dropyridazin-3 -y 1)- 1 H-indol-5-y l)piperidin- 1 -y 1)-N,N- dimethylacetamide (130); 2-(4-(3-isopropyl-2-(l,4,5-trimethyl-6-oxo-l,6- dihydropyridazin-3-yl)-lH-indol-5-yl)piperidin-l -yl)-N-methylacetamide (131); 6-(3- isopropyl-5-(l-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-2,4- dimethylpyridazin-3(2H)-one (188); 6-(3-isopropyl-5-(l -(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one (189); 6-(3-isopropyl-5-(l -methylpiperidin- 4-yl)-lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one (191); 6-(3-isopropyl-5-(l- isopropylpiperidin-4-yl)-lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one (192); 6-(3- isopropyl-5-(l-(tetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-2,4- dimethylpyridazin-3(2H)-one (193); 6-(3-isopropyl-5-(l -(tetrahydro-2H-pyran-4-yl) piperidin-4-yl)-lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one (194); 6-(3-isopropyl-5- (l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one (203); 6-(3-isopropyl-5-(l -(tetrahydro-2H-pyran-4-yl) piperidin-4-yl)-lH-indol-2-yl)-2,4,5- trimethylpyridazin-3(2H)-one (205); 6-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one (283); 6-(5-(l -(dimethylglycyl) piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one (294); and 6-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-2,4- dimethylpyridazin-3(2H)-one (311).
One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyrimidine-2,4(lH,3H)-dione (21).
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The invention encompasses all
combinations of the aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the
embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
DEFINITIONS
The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.
Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, "a" and "an" may refer to either one, or one or more.
As used herein, the phrase "compounds" refers to at least one compound. For example, a compound of Formula (I) includes a compound of Formula (I) and two or more compounds of Formula (I).
Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference.
Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.
In accordance with a convention used in the art,
Figure imgf000030_0001
is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
The terms "halo" and "halogen," as used herein, refer to F, CI, Br, and I.
The term "cyano" refers to the group -CN.
The term "amino" refers to the group -NH2.
The term "oxo" refers to the group =0.
The term "alkyl" as used herein, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g. , n-butyl, i-butyl, sec-butyl, and i-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3 -methylpentyl, and 4- methylpentyl. When numbers appear in a subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular group may contain. For example, "Ci-6 alkyl" denotes straight and branched chain alkyl groups with one to six carbon atoms.
The term "fluoroalkyl" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C1-4 fluoroalkyl" is intended to include Ci, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.
The term "chloroalkyl" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more chlorine atoms. For example, "C1-4 chloroalkyl" is intended to include Ci, C2, C3, and C4 alkyl groups substituted with one or more chlorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CCI3 and -CH2CCI3.
The term "cyanoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CH2CN, -CH2CH2CN, and CM cyanoalkyl.
The term "aminoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more amino groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and Ci-4 aminoalkyl. The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C M hydroxyalkyl.
The term "hydroxy-fluoroalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. For example, "hydroxy-fluoroalkyl"
includes -CHFCH2OH, -CH2CHFC(CH3)2OH, and C M hydroxy-fluoroalkyl.
The term "cycloalkyl," as used herein, refers to a group derived from a non- aromatic monocyclic or poly cyclic hydrocarbon molecule by removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in a subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C3-C6 cycloalkyl" denotes cycloalkyl groups with three to six carbon atoms.
The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (-OCH3). For example, "C1-3 alkoxy" denotes alkoxy groups with one to three carbon atoms.
The terms "fluoroalkoxy" and "-O(fluoroalkyl)" represent a fluoroalkyl group as defined above attached through an oxygen linkage (-0-). For example, "CM
fluoroalkoxy" is intended to include Ci, C2, C3, and C4 fluoroalkoxy groups.
The term "alkoxy alkoxy," as used herein, refers to an alkoxy group attached to the parent molecular moiety through an alkoxy group, for example, methoxymethoxy group (-OCH2OCH3). For example, "C1-4 alkoxyalkoxy" denotes alkoxy groups with one to four carbon atoms.
The term "benzyl," as used herein, refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group. The phenyl ring may be unsubstituted or may contain one or more substituents as valence allows.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The compounds of Formula (I) can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of Formula (I) as amorphous solids.
It should further be understood that solvates (e.g., hydrates) of the compounds of Formula (I) are also within the scope of the present invention. The term "solvate" means a physical association of a compound of Formula (I) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.
Various forms of prodrugs are well known in the art and are described in:
a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996);
b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);
c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 - 191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).
In addition, compounds of Formula (I), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formula (I) ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of Formula (I) are also contemplated herein as part of the present invention.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.
"Therapeutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor to TLR7/8/9, or effective to treat or prevent autoimmune and/or inflammatory disease states, such as SLE, IBD, multiple sclerosis (MS), Sjogren's syndrome, and rheumatoid arthritis.
As used herein, "treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease- state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
The compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 1 C and 14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. For example, methyl (- CH3) also includes deuterated methyl groups such as -CD3.
UTILITY
The human immune system has evolved to defend the body from microorganisms, viruses, and parasites that can cause infection, disease or death. Complex regulatory mechanisms ensure that the various cellular components of the immune system target the foreign substances or organisms, while not causing permanent or significant damage to the individual. While the initiating events are not well understood at this time, in autoimmune disease states the immune system directs its inflammatory response to target organs in the afflicted individual. Different autoimmune diseases are typically characterized by the predominate or initial target organ or tissues affected; such as the joint in the case of rheumatoid arthritis, the thyroid gland in the case of Hashimoto's thyroiditis, the central nervous system in the case of multiple sclerosis, the pancreas in the case of type I diabetes, and the bowel in the case of inflammatory bowel disease.
The compounds of the invention inhibit signaling through Toll-like receptor 7, or 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Accordingly, compounds of Formula (I) have utility in treating conditions associated with the inhibition of signaling through one or more of TLR7, TLR8, or TLR9. Such conditions include TLR7, TLR8, or TLR9 receptor associated diseases in which cytokine levels are modulated as a consequence of intracellular signaling.
As used herein, the terms "treating" or "treatment" encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease state, i.e., arresting its development; and/or (c) achieving a full or partial reduction of the symptoms or disease state, and/or alleviating, ameliorating, lessening, or curing the disease or disorder and/or its symptoms.
In view of their activity as selective inhibitors of TLR7, TLR8, or TLR9, the compounds of Formula (I) are useful in treating TLR7, TLR8, or TLR9 family receptor associated diseases, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis; auto-inflammatory diseases including CAPS, TRAPS, FMF, adult onset Still's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myelogenous leukemia, chronic myelogenous leukemia;
angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; infectious diseases such as sepsis, septic shock, and Shigellosis; neurodegenerative diseases such as Alzheimer's disease,
Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury, oncologic and viral diseases such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS, respectively.
More particularly, the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rej ections, fever and myalgias due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic
myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase syndase-2, and pemphigus vulgaris. Preferred methods of treatment are those wherein the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. Alternatively preferred methods of treatment are those wherein the condition is selected from ischemia reperfusion injury, including cerebral ischemia reperfusions injury arising from stroke and cardiac ischemia reperfusion injury arising from myocardial infarction. Another preferred method of treatment is one in which the condition is multiple myeloma.
In one embodiment, the compounds of Formula (I) are useful in treating cancer, including Waldenstrom's Macroglobulinemia (WM), diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneous diffuse large B cell lymphoma, and primary CNS lymphoma.
In addition, the TLR7, TLR8, or TLR9 inhibitors of the present invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin
endoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2), IL-1 , IL-6, IL-18, chemokines. Accordingly, additional TLR7/8/9 associated conditions include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by cancer, dental pain and arthritis pain. The inventive compounds also may be used to treat veterinary viral infections, such as lentivirus infections, including, but not limited to equine infectious anemia virus; or retrovirus infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.
The present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically-effective amount of at least one compound of Formula (I) or a salt thereof. "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit autoimmune disease or chronic inflammatory disease.
The methods of treating TLR7, TLR8, or TLR9 associated conditions may comprise administering compounds of Formula (I) alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions.
Accordingly, "therapeutically effective amount" is also intended to include an amount of the combination of compounds claimed that is effective to inhibit TLR7, TLR8, or TLR9 and/or treat diseases associated with TLR7, TLR8, or TLR9.
Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®); anti-malarials such as hydroxychloroquine; cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or RAPAMU E®) or derivatives thereof.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians ' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the
administration of the inventive compounds. The present invention also provides pharmaceutical compositions capable of treating TLR7/8/9 receptor-associated conditions, including IL-1 family receptor-mediated diseases as described above.
The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g. , excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
Accordingly, the present invention further includes compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier.
A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals.
Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent- containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g. , stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable
pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington 's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in its entirety.
Compounds in accordance with Formula (I) can be administered by any means suitable for the condition to be treated, which can depend on the need for site-specific treatment or quantity of Formula (I) compound to be delivered.
Also embraced within this invention is a class of pharmaceutical compositions comprising a compound of Formula (I) and one or more non-toxic, pharmaceutically - acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The compounds of Formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional components such as a lubricating agent, e.g. magnesium stearate and a disintegrating agent such as crospovidone. The carrier mixture may be filled into a gelatin capsule or compressed as a tablet. The pharmaceutical composition may be administered as an oral dosage form or an infusion, for example.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods.
Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations. Exemplary oral preparations, include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition in accordance with the invention can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.
A tablet can, for example, be prepared by admixing at least one compound of Formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc. Additionally, a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period. Exemplary water soluble taste masking materials, include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplary time delay materials, include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.
Hard gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.
Soft gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.
An aqueous suspension can be prepared, for example, by admixing at least one compound of Formula (I) with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension, include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, alginic acid, poly vinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, poly oxy ethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol;
condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxy ethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n- propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.
Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described hereinabove, and/or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an antioxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.
Dispersible powders and granules can, for example, be prepared by admixing at least one compound of Formula (I) with at least one dispersing and/or wetting agent; at least one suspending agent; and/or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents. An emulsion of at least one compound of Formula (I) thereof can, for example, be prepared as an oil-in-water emulsion. The oily phase of the emulsions comprising compounds of Formula (I) may be constituted from known ingredients in a known manner. The oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally-occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and/or an antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
The compounds of Formula (I) can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in- water microemulsions; and aqueous or oleaginous suspensions.
Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or mi cellar solubilization (i.e. Tween 80).
The sterile injectable preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of inj ectables.
A sterile injectable oil-in- water microemulsion can, for example, be prepared by 1) dissolving at least one compound of Formula (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Formula (I) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.
A sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1 ,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.
Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol poly ethylenegly col 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- poly oxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
The amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg/kg body weight, preferably between about 0.0025 and about 50 mg/kg body weight and most preferably between about 0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.
For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
Pharmaceutical compositions of this invention comprise at least one compound of Formula (I) and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Alternate compositions of this invention comprise a compound of the Formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a cardiovascular and/or inflammatory disorder (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat
cardiovascular and/or inflammatory disorder. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.
The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g. , for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product. The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.
The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g. , the United States Food and Drug
Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g. , paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g. , printed or applied).
METHODS OF PREPARATION
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
The compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts {Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999).
Compounds of Formula (I) may be prepared by reference to the methods illustrated in the following Scheme. As shown therein the end product is a compound having the same structural formula as Formula (I). It will be understood that any compound of Formula (I) may be produced by the schemes by the suitable selection of reagents with appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Constituents of compounds are as defined herein or elsewhere in the specification.
As shown in Scheme 1, compounds of Formula I may be produced, starting with the substituted 5-haloindoles (2). 2 can be prepared from the 3-formyl indoles (via reduction) or from the 3-H indoles, via alkylation. Transition metal catalyzed cross coupling of 2 and boronate 3 followed by olefin reduction and bromination affords 4, which can then be converted to the boronic ester 5. Transition metal catalyzed cross coupling of 5 with aryl halide 6 followed by Boc deprotection yields 7. Alkylation of 7 leads to the production of the compounds of Formula I.
Figure imgf000048_0001
where X can be CI, Br, I or OTf
Figure imgf000048_0002
2) Deprotection Alkylation
or acylation
Figure imgf000049_0001
ABBREVIATIONS
Ac acetyl
ACN acetonitrile
anhyd. anhydrous
aq. aqueous
BH3DMS boron dimethylsulfide
Bn benzyl
Bu butyl
Boc fert-butoxycarbonyl
CV Column Volumes
DBU l ,8-diazabicyclo[5.4.0]undec-7-ene
DCE dichloroethane
DCM dichloromethane
DMF dimethylformamide
DMSO dimethylsulfoxide
EtOAc ethyl acetate
Et ethyl
EtOH ethanol
Et3N triethylamine
H or Hi hydrogen
h, hr or hrs hour(s)
hex hexane
i iso
IPA isopropyl alcohol
HC1 hydrochloric acid
HPLC high pressure liquid chromatography LC liquid chromatography
M molar
mM millimolar
Me methyl
MeOH methanol
MHz megahertz
min. minute(s)
mins minute(s)
M+1 (M+H)+
MS mass spectrometry
n or N normal
NBS n-bromosuccinimide
nm nanometer
nM nanomolar
Pd/C palladium on carbon
PdCl2(dppf) [ 1 , -te(dipheny lphosphino)ferrocene] dichloropalladium(II)
Ph phenyl
Pr propyl
PSI pounds per square inch
Ret Time retention time
sat. saturated
SFC supercritical fluid chromatography
T3P propane phosphonic anhydride
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TsCl 4-toluenesulfonyl chloride
XPhos G2 Precatalyst chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l biphenyl)[2-(2'-amino-l, -biphenyl)]palladium(II)
Analytical and Preparative HPLC conditions:
QC-ACN-AA-XB: Column: Waters Acquity UPLC BEH C 18, 2.1 x 50 mm, 1. particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.
QC-ACN-TFA-XB: Column: Waters Acquity UPLC BEH C 18, 2.1 x 50 mm, 1.7-μπι particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.
Method Al: L3 Acquity: Column: (LCMS) UPLC BEH C18, 2.1 x 50 mm, 1.7 μηι particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98%B (to 1.5 min) 98%-2% B (to 1.6 min); Gradient Time: 1.6 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1 : UV at 220 nm; Detector 2: MS (ESI+).
Method Bl : L2 Aquity(4); Column: (LCMS) UPLC BEH C 18, 2.1 x 50 mm, 1.7 μηι particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98%B (to 1.5 min) 98%-2% B (to 1.5 min); Gradient Time: 1.8 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1 : UV at 220 nm; Detector 2: MS (ESI+).
Method CI SCP: Column: Waters Acquity UPLC BEH CI 8, 2.1 x 50 mm, 1.7-μηι particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate. Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
Method Dl SCP: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μηι particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
Method D2 SCP: Column: XBridge CI 8, 19 x 200 mm, 5-μηι particles;
Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Detection: UV at 220 nm. Method D3 SCP: Column: XBridge CI 8, 19 x 200 mm, 5-μηι particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 6-46% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Detection: UV at 220 nm.
Method El iPAC: Column: Waters Xbridge CI 8 4.6 x 50 mm 5 um particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate. Temperature: 50 °C; Gradient: 0- 100%) B over 1 minute; Flow: 4 mL/min; Detection: UV at 220 nm.
Method Fl iPAC: Column: Waters Acquity BEH C18 2.1x50 mm 1.7-μηι particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0- 100% B over 2.20 minutes; Flow: 0.800 mL/min; Detection: UV at 220 nm.
Waters Acquity SDS: Run Time: 2.20 min; Comment: Generic gradient; Solvent
Selection A: Al; Solvent Selection B: Bl ; Low Pressure Limit: 0 psi; High Pressure Limit: 15000 psi; Solvent Name A: 100% H20 w/0.05% TFA; Solvent Name B: 100% ACN w/0.05% TFA. (A): Column-Ascentis Express C18 (50X2.1 πιηι-2.7μηι) Mphase A: 10 mM NH4COOH in water: ACN (98:02); Mphase B: 10 mM NH4COOH in water: ACN (02:98), Gradient: 0-100% B over 3 minutes, Flow = 1 mL/min.
(B) : Waters Acquity BEH C18 (2.1 x 50 mm) 1.7 micron; Buffer: 5 mM ammonium acetate pH 5 adjusted with HCOOH, Solvent A: Buffer: ACN (95:5), Solvent B:
Buffer:ACN (5:95), Method:%B: 0 min-5%: 1.1 min -95%: 1.7 min-95%, Flow: 0.8 mL/min.
(C) : Column-Ascentis Express C18 (50X2.1 πιηι-2.7μηι) Mobile phase A: 0.1%HCOOH in water; Mobile phase B: ACN. Temperature: 50 °C; Gradient: 0-100% B over 3 minutes; Flow rate: 1.0 mL/min.
(D): Kinetex XB-C18 (75x3 mm) 2.6 micron; Solvent A: 10 mM ammonium formate in water: acetonitrile (98:02); Mobile Phase B: 10 mM ammonium formate in water:
acetonitrile (02:98); Temperature: 50 °C; Gradient: 0-100% B over 3 minutes; Flow rate: 1.1 rnL/min; Detection: UV at 220 nm.
(E) : Column: Ascentis Express CI 8 (50x2. l)mm, 2.7μηι; Mobile Phase A: 5:95 acetonitrile: water with 10 mM NEUOAc; Mobile Phase B: 95:5 acetonitrile: water with 10 mM NELtOAc; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min.
(F) : Column: Ascentis Express CI 8 (50x2. l)mm, 2.7μηι; Mobile Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; Temperature: 50 °C; Gradient: 0-100%B over 3 minutes; Flow: 1.1 mL/min.
(G) : Column: Waters Acquity UPLC BEH CI 8 (2.1 x 50 mm), 1.7 micron; Solvent A = 100% water with 0.05% TFA; Solvent B = 100% acetonitrile with 0.05% TFA; gradient =
2-98% B over 1 minute, then a 0.5-minute hold at 98% B; Flow rate: 0.8 mL/min;
Detection: UV at 220 nm.
Template 1 : tert-butyl 4-(2-bromo-3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate
Figure imgf000053_0001
Intermediate T-1A: 5-bromo-3-isopropyl-lH-indole
Figure imgf000053_0002
(T-1A)
A 250 mL round bottom flask was charged with triethylsilane (8.90 g, 77 mmol), trichloroacetic acid (6.25 g, 38.3 mmol) and toluene (50 mL). The solution was heated to 70 °C, then a solution of 5-bromo-lH-indole (5.0 g, 25.5 mmol) and acetone (2.247 mL, 30.6 mmol) in toluene (30 mL) was added drop wise via an addition funnel. The resulting brown solution was heated at 70 °C for 1.5 h. The solution was cooled to 10 °C, quenched with 10% sodium bicarbonate and diluted with diethyl ether. The organic layer was separated, dried, and concentrated under vacuum to afford crude compound. The crude was purified using silica gel chromatography eluting with 5% ethyl acetate in hexanes to afford 5-bromo-3-isopropyl-lH-indole (5.5 g, 23.10 mmol 95% yield) as an oil. LC retention time 1.42 min [D]. MS (E-) m/z: 238.2 (M+H). ¾ NMR (400 MHz, DMSO-de) δ 10.96 (br s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.15 (t, J=2.1 Hz, 1H), 3.12 (dtd, J=13.8, 6.8, 0.7 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H).
Intermediate T-1B: tert-butyl 4-(3-isopropyl-lH-indol-5-yl)-5,6-dihydropyridine-l(2H)- carboxylate
Figure imgf000054_0001
To a mixture of 5-bromo-3-isopropyl-lH-indole (5.5 g, 23.10 mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate
(7.50 g, 24.25 mmol) in a 250 mL round bottom flask were added THF (50 mL) followed by aqueous solution of potassium phosphate, dibasic (12.07 g, 69.3 mmol, 20 mL). The resulting reaction mixture was degassed for 10 minutes with nitrogen gas, then
PdCl2(dppf)-CH2Cl2 adduct, (0.472 g, 0.577 mmol) was added. The mixture was degassed again for 5 min. The resulting reaction mixture was heated at 75 °C for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL), poured into a separate funnel and was washed with water (2 x 50 mL), brine (50 mL), dried over sodium sulfate, and concentrated to afford crude product. The crude material was purified using silica gel chromatography, eluting with 15% ethyl acetate in hexane. The fractions were collected and concentrated to afford tert-butyl 4-(3-isopropyl-lH-indol-5- yl)-5,6-dihydropyridine-l(2H)-carboxylate (6.5 g, 83% yield) as an oil. LCMS retention time 1.21 min [B]. MS (E-) m/z: 339 (M-H). ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.94 (br. s., 1H), 7.67-7.61 (m, 1H), 7.33 (dd, J=8.6, 0.5 Hz, 1H), 7.27 (dd, J=8.6, 1.7 Hz, 1H), 6.98 (dd, J=2.3, 0.7 Hz, 1H), 6.02 (br. s., 1H), 4.12 (d, J=2.0 Hz, 2H), 3.70 (t, J=5.7 Hz, 2H), 3.24 (sptd, J=6.8, 0.7 Hz, 1H), 2.66 (br. s., 2H), 1.53 (s, 9H), 1.39 (d, J=6.8 Hz, 6H).
Intermediate T-1C: tert-butyl 4-(3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate H (T-1C)
To a solution of tert-butyl 4-(3-isopropyl-lH-indol-5-yl)-5,6-dihydropyridine- l(2H)-carboxylate (7.9 g, 23.20 mmol) in ethyl acetate (150 niL), under a nitrogen atmosphere, was added palladium on carbon (0.617 g, 0.580 mmol). The vessel was pimp/purged three times with nitrogen gas then evacuated. Hydrogen gas was introduced via a balloon and the mixture was stirred at room temperature for 5 hours. The suspension was filtered through celite and the filtrate was concentrated to afford crude compound. The crude residue was purified by ISCO using a 40 g silica column, eluting with 15% ethyl acetate in hexane. The combined fractions were collected and concentrated to afford tert-butyl 4-(3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (6.5 g, 82% yield) as a white solid. LCMS retention time 2.48 min [C]. MS (E-) m/z: 341 (M-H). ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.88 (br. s., IH), 7.48 (s, IH), 7.31 (d, J=8.3 Hz, IH), 7.06 (dd, J=8.3, 1.6 Hz, IH), 6.97 (d, J=1.8 Hz, IH), 4.29 (br. s., 2H), 3.22 (sptd, J=6.8, 0.5 Hz, IH), 2.86 (t, J=12.3 Hz, 2H), 2.77 (tt, J=12.1, 3.7 Hz, IH), 1.91 (d, J=13.0 Hz, 2H), 1.73 (qd, J=12.8, 4.6 Hz, 2H), 1.52 (s, 9H), 1.38 (d, J=7.0 Hz, 6H).
Template 1 : tert-but -(2-bromo-3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate
Figure imgf000055_0001
(Template- 1) To a solution of tert-butyl 4-(3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (6.3 g, 18.40 mmol) in DCE (60 mL) was added NBS (3.27 g, 18.40 mmol) dissolved in DCE (50 mL) drop wise via an addition funnel over 10 min at 0 °C. The resulting brown solution was stirred at room temperature for 20 min. The reaction was quenched with sodium sulfite solution (15 mL). The volatiles were removed and the residue was taken up in DCM (50 mL) and the aqueous layer was separated. The organic layer was dried over Na2S04 and concentrated to afford crude compound. The crude material was purified by ISCO using 40 g silica column. The compound eluted in 15% ethyl acetate in petroleum ether, the fractions were collected and concentrated to afford tert-butyl 4-(2- bromo-3-isopropyl-lH-indol-5-yl)piperidine-l -carboxylate (6.4 g, 83% yield) as a white solid. LCMS retention time 2.58 min [H] . MS (E") m/z: 367.2 (M-H). ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.88 (br. s., 1H), 7.48 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.3, 1.6 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 4.29 (br. s., 2H), 3.22 (sptd, J=6.8, 0.5 Hz, 1H), 2.86 (t, J=12.3 Hz, 2H), 2.77 (tt, J=12.1 , 3.7 Hz, 1H), 1.91 (d, J=13.0 Hz, 2H), 1.73 (qd, J=12.8, 4.6 Hz, 2H), 1.52 (s, 9H), 1.38 (d, J=7.0 Hz, 6H).
Template 2: tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indol-5-yl)piperi dine- 1 -carboxy late
Figure imgf000056_0001
a mixture of tert-butyl 4-(2-bromo-3-isopropyl-lH-indol-5-yl)piperidine-l- carboxylate (1.0 g, 2.373 mmol), 2-dicyclohexyphosphino-2',6'-dimethoxybiphenyl
(0.1 17 g, 0.285 mmol) and bis(benzonitrile)palladium(II)chloride (0.027 g, 0.071 mmol) in a 50 mL reaction tube was added dioxane (10 mL). The resulting reaction mixture was degassed for 10 min and then pinacolborane (0.456 g, 3.56 mmol) was added followed by dropwise addition of TEA (0.992 mL, 7.12 mmol). The solution was again degassed for 5 min. The resulting reaction mixture was heated at 85 °C for 3h. The reaction mixture was concentrated and the crude residue was dissolved in ethyl acetate (100 mL), poured into a separatory funnel and was washed thoroughly with water (2 x 250 mL). The organic layer was dried over Na2S04, filtered and the filtrate was concentrated under vacuum to afford the crude product. The residue was taken up in DCM (3 mL) .The crude was purified by combiflash system by eluting with 12% EtOAc /Pet ether.
Following concentration of the fractions, the product was isolated as a white gummy product (0.75 g, 67.5% yield). LCMS retention time 4.27 min [H]. MS (E-) m/z:
467.3(M-H). ¾ NMR (400 MHz, DMSO-de) δ 10.65 (s, 1H), 7.50 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.99 (dd, J=8.5, 1.3 Hz, 1H), 4.09 (br d, J=l l. l Hz, 2H), 3.71-3.61 (m, 1H), 2.91-2.66 (m, 3H), 1.77 (br d, J=11.7 Hz, 2H), 1.59-1.46 (m, 2H), 1.43 (s, 9H), 1.36 (d, J=7.1 Hz, 6H), 1.32 (s, 12H).
Template 3: tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-lH-indole-l- carboxylate
Figure imgf000057_0001
Tert-butyl 4-(3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (328 mg, 0.958 mmol) (T-1C) was dissolved in THF (7662 μΐ) in a 50 mL recovery flask containing a Teflon-covered stir bar. Di-tert-butyl dicarbonate (298 μΐ, 1.245 mmol) was added to the flask, followed by 4-dimethylaminopyridine (11.70 mg, 0.096 mmol). The flask was capped and stirred at room temperature for 16 h. Excess solvent was evaporated from the reaction mixture under reduced pressure. The residue was taken up in DCM (~ 3 mL) and purified by flash chromatography on a 24 g SiC column, eluting with 0%-50 % gradient using EtOAc and hexanes, on an ISCO Rf instrument to afford tert-butyl 5-(l- (tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-lH-indole-l-carboxylate (313.7 mg, 0.702 mmol, 73.3 % yield) as a colorless foam. LCMS of product; mass ion observed corresponds to (product - 2 x tBu) = 331.3, 1.51 min). ¾ NMR (400 MHz,
CHLOROFORM-d) δ 8.05 (d, J=6.2 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.33 (br. s., 1H), 7.17 (dd, J=8.6, 1.7 Hz, 1H), 4.29 (br. s., 2H), 3.13 (sptd, J=6.8, 0.9 Hz, 1H), 2.86 (t,
J=12.3 Hz, 2H), 2.77 (tt, J=12.0, 3.5 Hz, 1H), 1.90 (d, J=12.7 Hz, 2H), 1.80-1.70 (m, 2H), 1.68 (s, 9H), 1.52 (s, 9H), 1.36 (d, J=7.0 Hz, 6H).
Tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-lH-indole-l- carboxylate (100 mg, 0.226 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (73.8 μΐ, 0.362 mmol) were dissolved in THF (1808 μΐ) in a 2-dram vial containing a Teflon-covered stir bar. The vial was cooled to -20 °C (dry ice/NMP bath) under an N2 atmosphere. Lithium diisopropylamide (169 μΐ, 0.339 mmol) was added dropwise to the vial (via a syringe through the septum cap) over - 15 min. The reaction mixture was stirred at -20 °C for 1 h, then allowed to slowly warm to 10 °C. The reaction was quenched by addition of 1 M KHSO4 (2 mL), and the resulting mixture was extracted with EtOAc (3x2 mL). The combined organic exacts were dried over Na2S04, and filtered. Excess solvent was evaporated off under an N2 stream. The residue was taken up in DCM (2.5 mL) and purified by flash chromatography on a 4 g S1O2 column, eluting with 0%-50% gradient using EtOAc and hexanes, on an ISCO Rf instrument to afford tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-indole-l-carboxylate (112.9 mg, 0.189 mmol, 83 % yield) as a colorless foam, m/z, (observed M-2tBu+H+ = 457.2, M+H+ = 569.3). A mass ion corresponding to the starting material was not observed. ¾ NMR (400 MHz,
CHLOROFORM-d) δ 7.79 (d, J=8.6 Hz, 1H), 7.42 (d, J=1.5 Hz, 1H), 7.09 (dd, J=8.6, 1.6 Hz, 1H), 4.28 (br. s., 2H), 3.20 (spt, J=7.1 Hz, 1H), 2.85 (t, J=12.2 Hz, 2H), 2.74 (tt, J=12.1, 3.5 Hz, 1H), 1.89 (d, J=12.7 Hz, 2H), 1.75-1.69 (m, 2H), 1.68 (s, 9H), 1.51 (s, 9H), 1.44 (s, 12H), 1.42 (d, J=7.1 Hz, 6H).
Fragment 1 : 5-bromo-l,3-dimethylpyridin-2(lH)-one
Figure imgf000058_0001
To a mixture containing 5-bromo-3-methylpyridin-2(lH)-one (1.3 g, 6.91 mmol) and K2CO3 (2.87 g, 20.74 mmol) in DMF (20 mL) was added dropwise Mel (0.865 mL, 13.83 mmol). The reaction mixture was stirred for 16 h and diluted with ethyl acetate (150 mL). The mixture was filtered through a pad of celite to remove the solids and the filtrate was washed with aqueous 10% LiCl solution (3 X 30 mL). The aqueous washes were combined and back extracted with additional ethyl acetate (2X25 mL). The organic extracts were combined and washed with saturated aqueous NaCl solution (50 mL), dried (Na2S04), filtered and concentrated to afford a mixture of O-methylated (minor) and N- methylated (major) products. The crude product was dissolved in a small amount of DCM and charged to a 24 g ISCO silica gel column which was eluted over a 15 min gradient with 10%-100% hexanes/ethyl acetate to afford 5-bromo-l,3-dimethylpyridin- 2(lH)-one (1 g, 4.95 mmol, 71.6 % yield). LCMS MH+: 202. HPLC Ret. Time 0.64 min. Method: Method B l . ¾ NMR: (400 MHz, CHLOROFORM-d) δ 7.32 (d, J=2.6 Hz, 1H), 7.30-7.25 (J=2.6 Hz, 1H), 3.55 (s, 3H), 2.17 (s, 3H). Fragment 2: 5-bromo-l -isobutyl- -methylpyridin-2(lH)-one
Figure imgf000059_0001
To a 20 mL vial with a pressure relief septum containing 5-bromo-3- methylpyridin-2(lH)-one (250 mg, 1.330 mmol) were added DMF (2.659 mL), potassium carbonate (184 mg, 1.330 mmol) and 1 -bromo-2-methylpropane (182 mg, 1.330 mmol). The vial was sealed. The reaction mixture was stirred at 65 °C for 4 hours, and then at room temperature overnight. The contents of the vial were diluted with brine (20 mL) and extracted with ethyl acetate (3x 25 mL). The combined organic extracts were washed with water (10 mL), dried over sodium sulfate, filtered and concentrated to yield an oil. The oil was purified on an Isco silica gel column (24 g) eluting with 100% hexane to 100% ethyl acetate over 15 minutes. Like fractions were combined and concentrated under vacuum to afford 5-bromo-l -isobutyl-3-methylpyridin-2(lH)-one (175 mg, 0.717 mmol, 53.9 % yield). LCMS MH+: 244. HPLC Ret. Time 0.85 min. Method: Method Bl .
Fragment 3 : 5-Bromo-3-methyl-l -phenylpyridin-2(lH)-
Figure imgf000059_0002
(F3)
To a dried nitrogen flushed 50 mL round bottom flask containing 3A molecular sieves (100 mg) were added 5-bromo-3-methylpyridin-2(lH)-one (100 mg, 0.532 mmol), phenylboronic acid (46.3 mg, 0.380 mmol), copper (II) acetate (207 mg, 1.140 mmol), pyridine (92 μΐ, 1.140 mmol), and pyridine-N-oxide (108 mg, 1.140 mmol) in DCM (5427 μΐ). Air (passed over drying agent) was bubbled into the solution for 15 minutes. The flask was sealed and the reaction mixture was stirred at room temperature for 3 days. The solution was filtered, washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting solid was purified on an Isco silica gel column (12 g, 100% hexanes-100% EtOAc). Fractions were combined and concentrated under vacuum to afford 5-bromo-3-methyl-l -phenylpyridin-2(lH)-one (10 mg, 0.038 mmol, 9.97 % yield). LCMS MH+: 266. HPLC Ret. Time 0.83 min. Method Bl . Fragment 4: 5-Bromo-l,3,4-trimethylpyridin-2(lH)-one
_4)
Figure imgf000060_0001
To a mixture of 5-bromo-3,4-dimethylpyridin-2-amine (0.6 g, 2.98 mmol) in concentrated H2SO4 (2 mL) and water (15 mL) was added a solution of sodium nitrite (0.309 g, 4.48 mmol) in water (1.5 mL) at 0 °C. The mixture was allowed to equilibrate to room temperature and stirred for 1 h. The precipitate was filtered and washed with water and dried to afford 5-bromo-3,4-dimethylpyridin-2-ol (400 mg, 1.980 mmol, 66.3 % yield), m/z (203, M+H).
To a mixture containing 5-bromo-3,4-dimethylpyridin-2-ol (500 mg, 2.475 mmol) and K2CO3 (684 mg, 4.95 mmol) in DMF (5 mL) was added Mel (0.309 mL, 4.95 mmol). The reaction mixture was stirred for 20 h. The reaction mixture was diluted with ethyl acetate (100 mL) and the solids were filtered through a pad of celite. The filtrate was washed with aqueous 10% LiCl solution (3x20 mL). The aqueous washes were combined and back extracted with ethyl acetate (2x25 mL). The organic extracts were combined and washed with saturated aqueous NaCl solution (50 mL), dried (Na2S04), filtered and concentrated to afford a mixture of O-methylated (minor) and N-methylated products. The crude product was dissolved in a small amount of DCM and charged to a 12 g ISCO silica gel column which was eluted over a 15 min gradient with 10%- 100% hexanes/ethyl acetate to afford 5-bromo-l ,3,4-trimethylpyridin-2(lH)-one (430 mg, 1.990 mmol, 80% yield), m/z (218, M+H). LCMS MH+: 218. HPLC Ret. Time 0.70 min. Method B l . ¾ NMR : (400 MHz, CHLOROFORM-d) δ 7.39 (s, 1H), 3.54 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H).
Fragment 5 : 5-bromo-3-chloro-l ,6-dimethylpyridin-2(lH)-one
Figure imgf000061_0001
A solution containing 5-bromo-6-methylpyridin-2-ol (1 g, 5.32 mmol) and NCS (0.852 g, 6.38 mmol) in THF (20 mL) was heated at 60 °C for 2 h. Additional NCS (-100 mg) was added and the reaction mixture was heated for an additional 1 h, cooled to room temperature and concentrated to dryness. The residue was re-suspended in diethyl ether/hexanes (20 mL, 9/1), stirred and sonicated for lh. The solids were collected and rinsed with additional ether/hexanes mixture (20 mL, 9/1). The filtrate was re- concentrated -1/2 volume to afford second crop of 5-bromo-3-chloro-6-methylpyridin-2- ol (1 g total), m/z (224, M+H). The product was contaminated with -10% of a bis chlorinated material, m/z (268, M+H).
To a mixture containing crude 5-bromo-3-chloro-6-methylpyridin-2-ol (1.5 g,
6.74 mmol) and K2CO3 (1.9 g, 13.49 mmol) in DMF (10 mL) was added Mel (0.843 mL, 13.49 mmol). The reaction mixture was stirred for 20 h and diluted with ethyl acetate (100 mL). The resulting solids were filtered through a plug of celite. The filtrate was washed with aqueous 10% LiCl solution (2x30 mL) and saturated aqueous NaCl solution (10 mL). The aqueous washes were combined and extracted with ethyl acetate (50 mL) and the ethyl acetate layer washed again with 10% LiCl aqueous solution (1x20 mL) and saturated aqueous NaCl solution (10 mL). The organic extracts were combined, dried (Na2S04), filtered and concentrated. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel 40 g column which was eluted over a 15 min gradient with 5%-100% hexanes/ethyl acetate to afford impure 5-bromo-3-chloro-l ,6- dimethylpyridin-2(lH)-one (800 mg). LCMS MH+: 238. HPLC Ret. Time 0.72 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.65 (s, 1H), 3.68-3.66 (s, 3H), 2.53 (s, 3H). Fragment 6: 5-bromo-3-chloro-l-methylpyridin-2(lH)-one
Figure imgf000062_0001
(F_6)
5-bromo-3-chloropyridin-2(lH)-one (400 mg, 1.919 mmol) was stirred with iodomethane (350 μΐ, 2.303 mmol) and potassium carbonate (530 mg, 3.84 mmol) in DMF (6397 μΐ) in a 20 mL scintillation vial at room temperature for 3 h. The reaction mixture was partitioned between 1 : 1 water and ethyl acetate (-20 mL total volume). The organic phase was extracted with brine (2x10 mL), then dried over sodium sulfate and filtered. Excess solvent was evaporated from the filtered organic phase to yield 5-bromo- 3-chloro-l-methylpyridin-2(lH)-one (458.7 mg, 1.856 mmol, 97 % yield, 90% purity) as a white solid. LCMS MH+: 223.8. HPLC Ret. Time 0.64 min. Method Bl. ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.61 (d, J=2.6 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 3.61 (s, 3H).
Figure imgf000062_0002
Figure imgf000063_0001
Fragment 20: 5-chloro-l,3-dimethylpyrazin-2(lH)-one
Figure imgf000064_0001
)
A solution containing 3,5-dichloro-l-methylpyrazin-2(lH)-one (300 mg, 1.676 mmol) (CAS 87486-33-7), tetramethyltin (0.256 mL, 1.844 mmol) and
tetrakis(triphenylphosphine)palladium(0) (48.4 mg, 0.042 mmol) in DMF (2 mL) in a Biotage microwave vial was sealed with a Teflon-lined septa cap. The vial was evacuated under vacuum and backfilled with nitrogen gas, using a needle from a vacuum manifold. The procedure repeated and the nitrogen line removed. The vial was heated in a Biotage microwave at 150 °C for 20 min. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and washed with aqueous 10% NaF solution (2x10 mL) and saturated aqueous NaCl solution (1x10 mL), dried (Na2S04), filtered and concentrated. The crude product was dissolved in a small amount of DCM and charged to a 10 g ISCO silica gel column, placed on a Teledyne ISCO system and eluted over a 20 min gradient using 0%-100% hexanes/ethyl acetate eluent to afford 5- chloro-l,3-dimethylpyrazin-2(lH)-one (170 mg, 1.072 mmol, 64.0 % yield). LCMS MH+: 159.0. HPLC Ret. Time 0.52 min. Method Bl. ¾ NMR (400 MHz,
CHLOROFORM-d) δ 7.13 (bm, 1H), 3.52 (s, 3H), 2.48 (d, J=0.6 Hz, 3H). Fragment 21 : 6-Chloro-2,4,5-trimethylpyridazin-3(2H)-one
Figure imgf000064_0002
3,6-dichloro-4,5-dimethylpyridazine (1 g, 5.65 mmol) was suspended in water (10 mL) and powdered KOH (1.585 g, 28.2 mmol) was added. The mixture was heated at 120 °C for 2 h in a sealed pressure vessel, cooled to room temperature and acidified to pH 5 with concentrated aqueous HC1. The resulting solids were filtered and washed with water (~5 mL) and dried to afford pure 6-chloro-4,5-dimethylpyridazin-3-ol (700 mg, 4.41 mmol, 78 % yield), m/z (159, M+H).
To a mixture containing 6-chloro-4,5-dimethylpyridazin-3-ol (100 mg, 0.631 mmol) and K2CO3 (349 mg, 2.52 mmol) in DMF (1 mL) was added Mel (0.079 mL, 1.261 mmol). The mixture was stirred for 2 h, diluted with water (10 mL) and extracted with ethyl acetate (4x15 mL). The extracts were combined and washed with 10% LiCl (1x10 mL) and saturated aqueous NaCl solution (10 mL), dried, filtered and concentrated. The crude material was dissolved in a small amount of DCM and charged to an ISCO silica gel 12 g column, which was eluted over a 10 min gradient with 5%-100% hexanes/ethyl acetate to afford 6-chloro-2,4,5-trimethylpyridazin-3(2H)-one (100 mg, 0.579 mmol, 92% yield), m/z (173, M+H). LCMS MH+: 173. HPLC Ret. Time 0.68 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 3.76 (s, 3H), 2.27 (d, J=0.7 Hz, 3H), 2.24 (d, J=0.7 Hz, 3H).
Fragment 22: 6-Chloro-2-ethyl-4 -dimethylpyridazin-3(2H)-one
Figure imgf000065_0001
H3 (F_22)
To a solution containing 6-chloro-4,5-dimethylpyridazin-3-ol (100 mg, 0.631 mmol) (see fragment 16) and iodoethane (0.051 mL, 0.631 mmol) in DMF (2.5 mL) was added K2CO3 (349 mg, 2.52 mmol). The reaction mixture was stirred for 20 h, diluted with ethyl acetate (50 mL) and washed with water (1x20 mL) and aqueous 10% LiCl solution (2x10 mL). The aqueous fractions were washed, combined and back extracted with ethyl acetate (20 mL). The organic extracts were combined and washed with saturated aqueous NaCl solution, dried (Na2S04), filtered and concentrated. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel 120 g ISCO Column which was eluted over a 15 min gradient with 5%-100% hexanes/ethyl acetate to afford 6-chloro-2-ethyl-4,5-dimethylpyridazin-3(2H)-one (105 mg, 0.563 mmol, 89% yield). LCMS MH+: 187. HPLC Ret. Time 0.77 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 4.18 (q, J=7.1 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.42- 1.35 (t,7.1 Hz, 3H). Fragment 23 : 6-Chloro-2-ethyl-4-methylpyridazin-3(2H)-one
Figure imgf000066_0001
(F-23)
To a mixture containing 6-chloro-4-methylpyridazin-3(2H)-one (250 mg, 1.729 mmol) and K2CO3 (598 mg, 4.32 mmol) in DMF (2.5 mL) was added ethyl iodide (0.210 mL, 2.59 mmol). The reaction mixture was stirred at room temperature for 22 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3x40 mL). The combined extracts were washed with 10% LiCl (2x20 mL) and saturated aqueous NaCl solution (1x20 mL), dried (Na2S04), filtered and concentrated to afford crude product. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel 12 g ISCO column which was eluted over a 10 min gradient with 0%-100% hexanes/ethyl acetate to afford 6-chloro-2-ethyl-4-methylpyridazin-3(2H)-one (250 mg, 1.448 mmol, 84% yield), m/z (173, M+H). LCMS MH+: 173. HPLC Ret. Time 0.70 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.06 (q, J=1.2 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.21 (d, J=\ 2 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H).
Fragment 24: 5-Bromo-3-methoxy-l ,6-dimethylpyridin-2(lH)-one
Figure imgf000066_0002
A solution containing 5-bromo-3-methoxy-6-methylpyridin-2-amine (1 g, 4.61 mmol) in sulfuric acid (2 mL, 37.5 mmol) and 4 mL water was cooled in an ice bath. A solution of sodium nitrite (0.636 g, 9.21 mmol) in water (1 mL) was added dropwise and the ice bath was removed. The reaction mixture was stirred at room temperature for 1 h. Water (25 mL) was added and the mixture was cooled in an ice bath and stirred for 20 min. The resulting solids were filtered, washed with water and dried to afford 5-bromo-3- methoxy-6-methylpyridin-2-ol (700 mg, 3.21 mmol, 69.7% yield), m/z (220, M+H).
To a solution containing 5-bromo-3-methoxy-6-methylpyridin-2-ol (700 mg, 3.21 mmol) in DMF (7.5 mL) was added K2CO3 (887 mg, 6.42 mmol) followed by the addition of Mel (0.401 mL, 6.42 mmol). The mixture was stirred for 2 h, diluted with ethyl acetate (100 mL) and the solids filtered through a pad of celite. The filtrate was washed with aqueous 10% LiCl solution (3x25 mL), saturated aqueous NaCl solution (25 m), dried (Na2S04), filtered and concentrated. The crude product was dissolved in a small amount of DCM and charged to a 24 g ISCO silica gel column, which was eluted over a 15 min gradient with 5%-100% DCM/EtOAc to afford 5-bromo-3-methoxy-l,6- dimethylpyridin-2(lH)-one (525 mg, 2.262 mmol, 70.5 % yield). LCMS MH+: 233.9. HPLC Ret. Time 0.65 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 6.74 (s, 1H), 3.82 (s, 3H), 3.64 (s, 3H), 2.48 (s, 3H).
Fragment 25 : 5-Bromo-3-methoxy-l ,4-dimethylpyridin-2(lH)-one
Figure imgf000067_0001
(F_25)
To a mixture of 5-bromo-3-methoxy-4-methylpyridin-2-amine (0.45 g, 2.073 mmol) in concentrated H2SO4 (1 mL) and water (3 mL) was added a solution of sodium nitrite (0.215 g, 3.11 mmol) in water (1 mL) at 0 °C. The mixture was allowed to come to room temperature and stirred for 1 h. Ice cold water (10 mL) was added and the precipitate was filtered and washed with ice water and dried to afford 5-bromo-3- methoxy-4-methylpyridin-2-ol (250 mg, 1.147 mmol, 55.3% yield).
To a mixture containing 5-bromo-3-methoxy-4-methylpyridin-2-ol (250 mg, 1.147 mmol) and K2CO3 (396 mg, 2.87 mmol) in DMF (2.5 mL) was added Mel (0.143 mL, 2.293 mmol). The reaction mixture was stirred for 20 h and diluted with ethyl acetate (50 mL). The solids were filtered through a pad of celite and the filtrate washed with aqueous 10% LiCl solution (3x10 mL) and saturated aqueous NaCl solution (10 mL), dried (Na2S04), filtered and concentrated to afford crude product. The crude product was dissolved in a small amount of DCM and charged to a 12 g ISCO silica gel column, which was eluted over a 10 min gradient with 5%-100% hexanes/ethyl acetate to afford 5-bromo-3-methoxy-l ,4-dimethylpyridin-2(lH)-one (218 mg, 0.939 mmol, 82% yield). LCMS MH+: 233.9. HPLC Ret. Time 0.67 min. Method Bl . ¾ NMR (400 MHz, DMSO-de) δ 7.88 (s, 1H), 3.75 (s, 2H), 3.43 (s, 3H), 2.15 (s, 3H). Fragment 26: 5-Chloro-l -methyl-3-(l-methyl-lH-pyrazol-4-yl)pyridin-2(lH)-one
Figure imgf000068_0001
3-bromo-5-chloropyridin-2(lH)-one (Combi-Blocks, CAS: 137628-16-1, 170 mg, 0.816 mmol) was stirred with iodomethane (149 μΐ, 0.979 mmol) and potassium carbonate (564 mg, 4.08 mmol) in DMF (2719 μΐ) in a 20 mL vial for 2 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate (4 mL total volume). The aqueous phase was extracted with ethyl acetate (2x1.5 mL). The combined organic phases were extracted with brine (2x10 mL). Excess solvent was evaporated from the combined organic phases to afford 3-bromo-5-chloro-l- methylpyridin-2(lH)-one (151.8 mg, 0.662 mmol, 81 % yield) as a pale yellow solid. M+H+ = 221.9, 223.9. ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.75 (d, J=2.7 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 3.62 (s, 3H).
l -methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (31.1 mg, 0.149 mmol) and 3-bromo-5-chloro-l -methylpyridin-2(lH)-one (35 mg, 0.157 mmol) were weighed into a 1-dram vial. THF (1049 μΐ) was added to the vial, followed by 2 M aqueous tripotassium phosphate (236 μΐ, 0.472 mmol). The reaction mixture was degassed by bubbling nitrogen through the solution for 2 min. 2nd generation XPhos precatalyst (4.95 mg, 6.29 μηιοΐ) were added to the reaction mixture. The reaction mixture was placed under a nitrogen atmosphere and stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature and the aqueous phase was removed, and excess solvent was evaporated from the organic phase. The residue was taken up in DCM (3 mL) and purified by flash chromatography on a 4 g silica column, eluting with dichloromethane and methanol on an IS CO Rf instrument to afford 5-chloro-l -methyl-3- (l-methyl-lH-pyrazol-4-yl)pyridin-2(lH)-one (30.8 mg, 0.131 mmol, 83% yield) as a pale yellow solid. LCMS MH+: 224.0. HPLC Ret. Time 0.63 min. Method B l . ¾ NMR (400 MHz, CHLOROFORM-d) δ 8.36 (s, 1H), 7.89-7.83 (m, 1H), 7.57 (d, J=2.7 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 3.94 (s, 3H), 3.60 (s, 3H). Fragment 27: 5-Chloro-l ,4-dimethyl-3-(l -methyl-lH-pyrazol-4-yl)pyridin-2(lH)-one
Figure imgf000069_0001
3-bromo-5-chloro-4-methylpyridin-2-ol (Combi-Blocks, CAS: 1199773-45-9, 170 mg, 0.764 mmol) was stirred with iodomethane (140 μΐ, 0.917 mmol) and potassium carbonate (528 mg, 3.82 mmol) in DMF (2547 μΐ) in a 20 mL vial at room temperature for 40 min. The reaction mixture was partitioned between water and ethyl acetate (4 mL total volume), and the aqueous phase was extracted with ethyl acetate (2x1.5 mL). The combined organic phases were extracted with brine (2x10 mL). Excess solvent was evaporated from the combined organic phases to afford 3-bromo-5-chloro-l,4- dimethylpyridin-2(lH)-one (217.2 mg, 0.735 mmol, 96 % yield) as a pale yellow solid, m/z (237.9, 239.9, M+H). ¾ NMR: (400 MHz, METHANOLS) δ 7.89 (s, 1H), 3.61 (s, 3H), 2.50 (s, 3H).
l -Methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (31.7 mg, 0.152 mmol) and 3-bromo-5-chloro-l,4-dimethylpyridin-2(lH)-one (30 mg, 0.127 mmol) were weighed into a 1-dram vial. THF (846 μΐ) was added to the vial, followed by 2 M aqueous tripotassium phosphate (190 μΐ, 0.381 mmol). The reaction mixture was degassed by bubbling nitrogen through the solution for 2 min. 2nd Generation XPhos precatalyst (3.99 mg, 5.07 μηιοΐ) was added to the reaction mixture. The reaction mixture was placed under a nitrogen atmosphere and stirred at 60 °C for 20 h. The aqueous phase was removed, and excess solvent was evaporated from the organic phase. The residue was taken up in DCM (3 mL) and purified by flash chromatography on a 4 g silica column, eluting with ethyl acetate and hexanes on an Isco Rf instrument. The product did not elute, so the column was then eluted with 1 -15% MeOH in dichloromethane. Excess solvent was evaporated from the product-containing fractions to afford 5-chloro-l ,4- dimethyl-3-(l -methyl-lH-pyrazol-4-yl)pyridin-2(lH)-one (12.8 mg, 0.053 mmol, 41.6 % yield) as a white solid. LCMS MH+: 238.0. HPLC Ret. Time 0.64 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.85 (s, 1H), 7.62 (s, 1H), 7.33 (s, 1H), 3.96 (s, 3H), 3.56 (s, 3H), 2.39 (s, 3H). Fragment 28: 5-Bromo-3-chloro-l-ethylpyridin-2(lH)-one
Figure imgf000070_0001
5-bromo-3-chloropyridin-2(lH)-one (150 mg, 0.720 mmol) was stirred with iodoethane (69.4 μΐ, 0.864 mmol) and potassium carbonate (497 mg, 3.60 mmol) in DMF (2399 μΐ) in a 20 mL vial containing a Teflon-coated stir bar at room temperature for 19 h. The reaction mixture was partitioned between water and ethyl acetate (8 mL total volume). The aqueous phase was extracted with ethyl acetate (2x2 mL). The combined organic phases were then dried (Na2S04), filtered and concentrated to afford 5-bromo-3- chloro-l-ethylpyridin-2(lH)-one (113.3 mg, 0.383 mmol, 53.3% yield) as a white solid. LCMS MH+: 237.9. HPLC Ret. Time 0.72 min. Method Bl.
Fragment 29: 5-Bromo-3-chloro-l,4-dimethylpyridin-2(lH)-one
Figure imgf000070_0002
(F_29)
5-bromo-4-methylpyridin-2-ol (1.00 g, 5.32 mmol) and N-chlorosuccinimide (0.473 mL, 5.85 mmol) were suspended in DCM (21.27 mL) in a 40 mL scintillation vial. The reaction mixture was stirred at room temperature for 3 h, then at 40 °C for 17 h. The reaction mixture was heated to 50 °C for 30 min, then allowed to cool to room
temperature. The reaction mixture was washed with water (2x10 mL) and then brine (1x5 mL). The yellow solid began to crash out of the organic solution after the second aqueous wash. Excess solvent was evaporated from the organic phase. The resulting residue was taken up in DMF (15 mL) in a 40 mL scintillation vial. Potassium carbonate (1.470 g, 10.64 mmol) and iodomethane (1.200 mL, 7.89 mmol) were added to the vial, and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between water and ethyl acetate, total volume ~ 30 mL. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2x10 mL). The combined organic phases were dried over sodium sulfate, filtered, and excess solvent was evaporated off. The residue was taken up in DCM/MeOH and dried onto silica, then purified by flash chromatography on a 24 g silica column, eluting with ethyl acetate and hexanes on an ISCO Rf instrument. The product-containing fractions were pooled and solvent was evaporated off to yield 5-bromo-3-chloro-l,4-dimethylpyridin- 2(lH)-one (1.0025 g, 4.03 mmol, 76% yield) as a yellow-orange solid. LCMS MH+:
237.8. HPLC Ret. Time 0.70 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.46 (s, 1H), 3.60 (s, 3H), 2.46 (s, 3H).
Fragment 30: 5-Bromo-l-(2-hydroxy-2-methylpropyl)-3-methylpyridin-2(lH)-one
Figure imgf000071_0001
To a 20 mL vial fitted with a Teflon lined septum were added 5-bromo-3- methylpyridin-2(lH)-one (100 mg, 0.532 mmol), DMF (1064 μί), potassium carbonate (73.5 mg, 0.532 mmol), and 2,2-dimethyloxirane (38.3 mg, 0.532 mmol). The vial was sealed. The reaction mixture was stirred at 65 °C for 3 h. The reaction mixture was cooled to room temperature and stirred for 20 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3x5 mL). Organic layers are combined, concentrated and purified by ISCO (12 g silica, 100% hexanes-100% ethyl acetate). Like fractions were combined and concentrated under vacuum to afford 5-bromo-l-(2- hydroxy-2-methylpropyl)-3-methylpyridin-2(lH)-one (101 mg, 0.369 mmol, 69.4 % yield). LC MS at t=peak #1, 0.67 min. (m+1 = 260) showed one major product that was consistent with Fragment 30. LCMS MH+: 260. HPLC Ret. Time 0.67 min. Method Bl.
Fragment 31 A:
Figure imgf000071_0002
(F-31)
To a mixture of 5-bromo-l,3-dimethylpyridin-2(lH)-one (300 mg, 1.485 mmol) (Fl) and NBS (264 mg, 1.485 mmol) in CC (20 mL) was added AIBN (24.38 mg, 0.148 mmol). The reaction mixture was heated at 90 °C for 1 hour and then cooled to room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCC . The organic layer was dried with MgS04, filtered and concentrated to afford 5-bromo-3-(bromomethyl)-l-methylpyridin-2(lH)-one (420 mg, 1.4 mmol, 100% yield). ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.58 (d, J=2.6 Hz, 1H), 7.46 (d, J=2.6 Hz, 1H), 4.43 (s, 2H), 3.59 (s, 3H).
To a mixture of MeOH (0.079 mL, 1.950 mmol) in THF (5 mL) was added sodium hydride (90 mg, 2.250 mmol). After stirring 30 minutes, 5-bromo-3- (bromomethyl)-l-methylpyridin-2(lH)-one (421 mg, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried with MgS04, filtered and concentrated. The crude material was purified on a silica gel cartridge (24 g) using an ethyl acetate/hexane gradient (0-100% ethyl acetate over 12.5 min) to afford 5-bromo-3-(methoxymethyl)-l - methylpyridin-2(lH)-one (160 mg, 0.689 mmol, 46.0% yield). LCMS MH+: 217.9.
HPLC Ret. Time 0.64 min. Method Acquity. ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.50 (dt, J=2.8, 1.3 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 4.44-4.36 (m, 2H), 3.55 (s, 3H), 3.49 (s, 3H).
The following fragments were prepared according to the general procedures for the above fragments, using the indicated starting materials and synthetic methods. The HPLC method was Method Bl .
TABLE 1
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
EXAMPLE 1
5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one
Figure imgf000075_0002
To a mixture containing 5-bromo-l -methylpyridin-2(lH)-one (15.05 mg, 0.080 mmol), tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH- indol-5-yl)piperidine-l-carboxylate (25 mg, 0.053 mmol), and Xphos Pd G2 (2.100 mg, 2.67 μηιοΐ) in a screw cap vial was added THF (1 mL) followed by an aqueous solution of tripotassium phosphate (100 μί, 0.300 mmol). The vial was fitted with a Teflon lined septum cap. The vial was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The evacuation procedure was repeated three times. The needle was removed and the vial was heated at 65 °C for 18 h. The reaction mixture was concentrated to dryness and treated with TFA (1 mL) for 30 min to facilitate the removal of the tert-butyloxycarbonyl group. The reaction mixture was re- concentrated to dryness and re-dissolved in DMF (2 mL). The sample was filtered through an Acrodisc, 13 mm, 0.45 micron nylon membrane syringe filter and was purified via preparative LC/MS with using condition Method D2 to afford 5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l -methylpyridin-2(lH)-one (12 mg, 0.034 mmol, 64.3% yield). LCMS MH+: 350. HPLC Ret. Time 0.58 min. Method Bl . ¾ NMR (500 MHz, DMSO-de) δ 10.84 (s, IH), 7.81 (d, J=2.1 Hz, IH), 7.53 (dd, J=9.3, 2.3 Hz, IH), 7.47 (s, IH), 7.23 (d, J=8.2 Hz, IH), 6.94 (d, J=8.3 Hz, IH), 6.52 (d, J=9.3 Hz, IH), 3.52 (s, 3H), 3.19-3.09 (m, 2H), 2.77-2.66 (m, 2H), 1.84 (m, 3H), 1.80-1.75 (m, 2H), 1.72-1.59 (m, 2H), 1.39 (d, J=7.0 Hz, 6H).
EXAMPLE 2
5 -(3 -isopropy 1-5 -(pip lpyridin-2(l H)-
Figure imgf000076_0001
Intermediate 2A: tert-butyl 4-(2-(l,5-dimethyl-6-oxo l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidine-l-carboxylate
Figure imgf000076_0002
(2A) To a mixture containing tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indol-5-yl)piperidine-l -carboxylate (2434 mg, 5.20 mmol), 5- bromo-l ,3-dimethylpyridin-2(lH)-one (1000 mg, 4.95 mmol), and Xphos Pd G2 (97 mg, 0.124 mmol) in a screw cap vial was added THF (25 mL) followed by an aqueous solution of potassium phosphate, tribasic (4.95 mL, 14.85 mmol). The vial was fitted with a Teflon lined septum cap. The vial was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The evacuation procedure was repeated three times. The needle was removed and the vial was heated at 65 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaCl solution (10 mL), dried (Na2S04), filtered and concentrated to afford crude material. The crude product was dissolved in a small amount of DCM and charged to a 40 g ISCO silica gel column, which was eluted over a 15 min gradient with 5%-100% hexanes/ethyl acetate to afford tert-butyl 4-(2-(l,5-dimethyl-6-oxo-l ,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl) piperidine-l -carboxylate, 2.1 g (90 %yield) m/e (464, M+1).
Example 2:
The purified tert-butyl 4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidine-l-carboxylate was dissolved in DCM (10 mL) and treated with TFA (10 mL). The reaction mixture was stirred for 30 min and concentrated to dryness. The residue was treated with saturated aqueous ammonium hydroxide (20 mL) and stirred for 30 min. The resulting fine suspension was filtered and rinsed with additional ammonium hydroxide and dried to afford 5-(3-isopropyl-5-(piperidin-4-yl)- lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (1.55 g, 4.26 mmol, 86 %yield) as a yellow solid. LCMS MH+: 364. HPLC Ret. Time 0.63 min. Method B l . ¾ NMR (400 MHz, DMSO-de) δ 10.80 (s, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.48 (s, 1H), 7.44 (dd, J=2.3, 1.1 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 6.94 (dd, J=8.4, 1.5 Hz, 1H), 3.91 (s, 1H), 3.54 (s, 3H), 3.21-3.10 (m, 3H), 2.77-2.65 (m, 3H), 1.84 (s, 3H), 1.82-1.62 (m, 4H), 1.41 (s, 3H), 1.39 (s, 3H).
EXAMPLE 3
5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)-one
Figure imgf000078_0001
Intermediate 3 A: tert-butyl 4-(2-(5-chloro-l,2-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate
Figure imgf000078_0002
To a mixture containing tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indol-5-yl)piperidine-l-carboxylate (1.0 g, 2.135 mmol), 5- bromo-3-chloro-l,6-dimethylpyridin-2(lH)-one (0.606 g, 2.56 mmol), and Pd(dppf)Cl2 (0.078 g, 0.107 mmol) in a screw cap vial was added THF (10 mL) followed by the addition of 3 M aqueous solution of potassium phosphate, tribasic (2.135 mL, 6.40 mmol). The vial was fitted with a Teflon lined septum cap. The vial was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 65 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and washed with saturated aqueous NaCl solution (5 mL), dried (Na2S04), filtered and concentrated to afford crude material. The crude product was dissolved in a small amount of DCM and charged to a 80 g ISCO column which was eluted over a 20 min gradient with 5%-100% hexanes/ethyl acetate to afford tert-butyl 4-(2-(5-chloro-l,2-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH- indol-5-yl) piperi dine- 1-carboxy late, m/z (448.2, M+H), which was contaminated with dimer, m/z (804, M+H), 700 mg.
Example 3 :
To a mixture containing crude tert-butyl 4-(2-(5-chloro-l,2-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (25 mg, 0.050 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.762 mg, 2.510 μιτιοΐ), and lithium chloride (4.26 mg, 0.100 mmol) in a screw cap vial was added DMF (0.5 mL) followed by the addition of tetramethyltin (0.014 mL, 0.100 mmol). The vial was fitted with a Teflon lined septum cap and the system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 100 °C for 6 h. Additional Pd catalyst (~1 mg) and tetramethyl tin (20 μί) were added and the reaction mixture was heated for an additional 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL) and washed with 10% aqueous LiCl solution (3x2 mL), dried (Na2S04), filtered and concentrated.
The crude tert-butyl 4-(3-isopropyl-2-(l,2,5-trimethyl-6-oxo-l,6-dihydropyridin-
3-yl)-lH-indol-5-yl)piperidine-l-carboxylate was suspended in DCM/TFA (1/1) (1 mL) for 30 min to facilitate the removal of the tert-butyloxycarbonyl group. The reaction mixture was concentrated and the crude material was purified via preparative HPLC/MS. Fractions containing the product were combined and dried via centrifugal evaporation to afford TFA salt. The material was free based by suspending the salt in concentrated ammonium hydroxide (1 mL) and stirring for 20 min. The solids were filtered and dried to afford 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)- one (5 mg, 0.013 mmol, 25% yield). LCMS MH+: 378. HPLC Ret. Time 0.63 min. Method Bl . ¾ NMR (400 MHz, METHANOLS) δ 7.56-7.52 (m, 1H), 7.34 (s, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.03 (dd, J=8.4, 1.3 Hz, 1H), 3.69 (s, 3H), 3.23-3.15 (m, 2H),
3.01 -2.90 (m, 1H), 2.85-2.70 (m, 3H), 2.31 (s, 3H), 2.16 (s, 3H), 1.95-1.87 (m, 2H), 1.85- 1.71 (m, 2H), 1.44-1.33 (m, 6H).
The following examples were prepared according to the general procedures for Examples 1 and 2 using the indicated fragment.
TABLE 2
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
EXAMPLE 50
5-(3-isopropyl-5-(pipe '-bipyridin]-2(lH)-one
Figure imgf000087_0002
tert-Butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-l -methyl-6-oxo- l ,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l -carboxylate (30 mg, 0.051 mmol) and 3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridine (21.06 mg, 0.103 mmol) were weighed into a 1-dram vial. THF (0.514 mL) was added to the vial, followed by aqueous tripotassium phosphate (2 M, 0.103 mL, 0.205 mmol). The reaction mixture was degassed by bubbling nitrogen through the solution for 2 min. Second generation XPhos precatalyst (1.212 mg, 1.541 μηιοΐ) was added and the reaction mixture was placed under a nitrogen atmosphere and stirred at 65 °C for 3 h. The reaction mixture was cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate (~ 2 mL each), separated, and the aqueous phase was extracted with ethyl acetate (2x2 mL). Excess solvent was evaporated from the organic phase. The resulting residue was Boc-deprotected with 2: 1 trifluoroacetic acid/dichloromethane (1.2 mL, 0.051 mmol), stirring for 45 min at room temperature. Toluene (~0.1 mL) was added, and excess solvent was evaporated from the reaction. The crude material was purified via preparative LC/MS. Fractions containing the product were combined and dried via centrifugal evaporation to afford 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methyl-[3,3'-bipyridin]-2(lH)-one (9.4 mg, 0.021 mmol, 40% yield, 94% purity). LCMS MH+: 427.3. HPLC Ret. Time 1.01 min. Method QC-ACN-TFA-XB. ¾ NMR (500 MHz, DMSO-de) δ 1 1.00 (s, IH), 9.08 (br. s., IH), 8.42 (d, J=8.2 Hz, 2H), 7.94 (s, IH), 7.90 (d, J=2.4 Hz, IH), 7.66 (dd, J=7.8, 5.0 Hz, IH), 7.53 (s, IH), 7.31 (d, J=8.2 Hz, IH), 6.98 (d, J=8.5 Hz, IH), 3.59-3.49 (m, 3H), 3.40 (d, J=1 1.9 Hz, 2H), 3.24 (dt, J=14.0, 6.9 Hz, IH), 3.09-2.98 (m, 2H), 2.96-2.89 (m, IH), 2.01-1.93 (m, 2H), 1.93-1.81 (m, 2H), 1.43 (d, J=7.0 Hz, 6H).
The following examples were prepared according to the general procedure for Example 50 using the indicated starting material.
TABLE 3
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
EXAMPLE 65
5-(3-isopropyl-5-(piperi ,3'-bipyridin]-2(lH)-one
Figure imgf000091_0001
Intermediate 65 A: tert-butyl 4-(2-(5-chloro-l ,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-ind -5-yl)piperidine-l-carboxylate
Figure imgf000091_0002
5-bromo-3-chloro-l,4-dimethylpyridin-2(lH)-one (0.100 g, 0.423 mmol) was coupled to tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH- indol-5-yl)piperi dine- 1 -carboxy late (0.172 g, 0.368 mmol) as described above for Intermediate 2A to afford tert-butyl 4-(2-(5-chloro-l ,4-dimethyl-6-oxo-l ,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (149.3 mg, 0.285 mmol, 77% yield) as a pale yellow solid. LCMS MH+: 498.2. HPLC Ret. Time 1.12 min QC-ACN-TFA-XB. ¾ NMR (400 MHz, CHLOROFORM-d) δ 9.03 (s, IH), 7.60 (s, IH), 7.43 (d, J=8.3 Hz, IH), 7.18 (s, IH), 7.12 (dd, J=8.4, 1.5 Hz, IH), 4.38-4.22 (m, 2H), 3.60 (s, 3H), 2.96 (quin, J=7.1 Hz, IH), 2.87 (t, J=12.2 Hz, 2H), 2.79 (tt, J=12.1 , 3.2 Hz, IH), 2.17 (s, 3H), 1.93 (d, J=12.5 Hz, 2H), 1.75 (qd, J=12.6, 4.0 Hz, 2H), 1.52 (s, 9H), 1.39 (d, J=7.0 Hz, 6H).
Example 65 :
tert-Butyl 4-(2-(5-chloro-l,4-dimethyl-6-oxo-l ,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (134.3 mg, 0.270 mmol) was coupled to pyridin-3-ylboronic acid (66.3 mg, 0.539 mmol). Next, tert-butyl 4-(2-(l,4-dimethyl- 2-oxo-l,2-dihydro-[3,3'-bipyridin]-5-yl)-3-isopropyl-lH-indol-5-yl)piperidine-l- carboxylate (16.2 mg, 0.030 mmol) was deprotected as described above for Example 50 to afford 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethyl-[3,3'-bipyridin]- 2(lH)-one (12.0 mg, 0.026 mmol, 85% yield for the deprotection, 94% purity). LCMS MH+: 441.3. HPLC Ret. Time 0.78 min. QC-ACN-TFA-XB. ¾ NMR (500 MHz, DMSO-de) δ 10.81 (s, 1H), 8.53 (br. s., 1H), 8.44 (br. s., 1H), 7.74 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.48 (br. s., 1H), 7.47 (d, J=7.7 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 3.52 (br. s., 3H), 3.17 (s, 2H), 3.03-2.94 (m, 1H), 2.72 (br. s., 3H), 1.79 (s, 6H), 1.71 (br. s., 2H), 1.34 (br. s., 6H).
EXAMPLE 66
3-isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one
Figure imgf000092_0001
Intermediate 66A: tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-l- methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l-carboxylate
Figure imgf000092_0002
5-Bromo-3-chloro-l-methylpyridin-2(lH)-one (0.390 g, 1.754 mmol) and tert- butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indole-l-carboxylate (0.950 g, 1.671 mmol) were weighed into a 40 mL scintillation vial containing a Teflon-coated stir bar and equipped a pressure- release cap. THF (8.35 mL) was added to the vial, followed by tripotassium phosphate (2.506 mL, 5.01 mmol). The reaction mixture was degassed by bubbling N2 through the solution for 5 min. 2nd generation XPhos precatalyst (0.039 g, 0.050 mmol) was added to the reaction mixture. The reaction mixture was placed under an N2 atmosphere and stirred at 65 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and the organic layer was isolated, dried (Na2S04), filtered and concentrated. The residue was taken up in DCM (~ 5 mL) and purified by flash chromatography on a 24 g silica column, eluting with 20-100% gradient using ethyl acetate and hexanes to afford tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5- chloro-l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l-carboxylate (915.5 mg, 1.254 mmol, 75% yield) as a yellow-orange solid. ¾ NMR indicted impurities. ¾ NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d, J=8.7 Hz, 1H), 7.54 (d, J=1.3 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.22 (dd, J=8.7, 1.7 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 4.29 (br. s., 2H), 3.69 (s, 3H), 2.99 (spt, J=7.1 Hz, 1H), 2.87 (t, J=12.0 Hz, 2H), 2.78 (tt, J=12.0, 3.4 Hz, 1H), 1.90 (d, J=12.3 Hz, 2H), 1.72 (qd, J=12.7, 3.8 Hz, 2H), 1.52 (s, 9H), 1.38 (d, J=7.1 Hz, 6H), 1.26 (s, 9H).
Intermediate 66B: tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(l- methy l-6-oxo-5-(prop- 1 -en-2-y 1)- 1 ,6-dihy dropy ridin-3 -y 1)- lH-indole- 1 -carboxy late
Figure imgf000093_0001
Tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-l-methyl-6-oxo- l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l-carboxylate (50 mg, 0.086 mmol) and 4,4,5, 5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (31.6 mg, 0.188 mmol) were weighed into a 1-dram vial containing a Teflon-coated stir bar and equipped a pressure- release cap. THF (856 μΐ) was added to the vial, followed by aqueous 2 M tripotassium phosphate (128 μΐ, 0.257 mmol). The reaction mixture was degassed by vacuum-purge with nitrogen (3x). Second generation XPhos precatalyst (2.020 mg, 2.57 μιτιοΐ) was added to the reaction mixture. The reaction mixture was placed under a nitrogen atmosphere and stirred at 65 °C for 17 h. The reaction mixture was cooled to room temperature. The aqueous phase was removed, and excess solvent was evaporated from the organic phase. The resulting residue was taken up in DCM (3 mL) and purified by flash chromatography on a 4 g silica column, eluting with ethyl acetate and hexanes to afford tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(l-methyl-6- oxo-5 -(prop- 1 -en-2-y 1)- 1 ,6-dihy dropy ridin-3-yl)- 1 H-indole- 1 -carboxy late (38.0 mg, 0.058 mmol, 67.7% yield) as a clear, pale yellow glass, m/z (590.1, M+H). ¾ NMR (400 MHz, CHLOROFORM-d) δ 8.19 (d, J=8.7 Hz, 1H), 7.56-7.53 (m, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.23-7.19 (m, 2H), 5.87 (d, J=1.7 Hz, 1H), 5.30-5.27 (m, 1H), 4.30 (d, J=8.7 Hz, 2H), 3.64 (s, 3H), 3.02 (spt, J=7.1 Hz, 1H), 2.86 (t, J=12.3 Hz, 2H), 2.78 (tt, J=12.1, 3.4 Hz, 1H), 2.15-2.12 (m, 3H), 1.90 (d, J=12.2 Hz, 2H), 1.72 (qd, J=12.7, 3.5 Hz, 2H), 1.52 (s, 9H), 1.41 (s, 9H), 1.38 (d, J=7.1 Hz, 6H). Example 66:
Tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(l-methyl-6- oxo-5-(prop-l-en-2-yl)-l,6-dihydropyridin-3-yl)-lH-indole-l-carboxylate (19 mg, 0.032 mmol) was dissolved in MeOH (0.322 mL) and transferred into the vial containing the 5% Pd on carbon (20 mg, 0.032 mmol) under a nitrogen atmosphere. The suspension was stirred and kept under a nitrogen atmosphere while triethylsilane (0.051 mL, 0.322 mmol) was added dropwise via syringe over ~ 5 min. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite, flushing with MeOH. Excess solvent was evaporated from the reaction mixture to yield a pale yellow oil.
The intermediate oil was Boc-deprotected with 2: 1 trifluoroacetic
acid/dichloromethane (1.2 mL, 0.032 mmol) for 40 min. Toluene (-0.2 mL) was added, and excess solvent was evaporated from the reaction mixture. The resulting residue was taken up in DMF (1.5 mL) and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19x200 mm, 5-μπι particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5- minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 3-isopropyl-5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (4.5 mg, 10.9 μιηοΐ, 34% yield, 95% purity). LCMS MH+: 392.3. HPLC Ret. Time 1.29 min. Method QC-ACN- TFA-XB. ¾ NMR (500 MHz, DMSO-de) δ 10.86 (br. s., 1H), 7.67 (br. s., 1H), 7.48 (br. s., 1H), 7.34 (br. s., 1H), 7.25 (d, J=8.0 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 3.17 (br. s., 2H), 3.12-3.03 (m, IH), 2.75 (d, J=11.6 Hz, 3H), 1.83 (br. s., 6H), 1.75 (d, J=13.9 Hz, 3H), 1.40 (d, J=6.6 Hz, 6H), 1.16 (d, J=6.6 Hz, 6H).
EXAMPLE 67
3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one
Figure imgf000095_0001
Intermediate 67A: tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(l- methyl-6-oxo-5-vinyl-l,6-dihydropyridin-3-yl)-lH-indole-l-carboxylate
Figure imgf000095_0002
Intermediate 67 A was prepared according to the general procedure for
Intermediate 66B substituting 4,4,5, 5-tetramethyl-2-vinyl-l,3,2-dioxaborolane for 4,4,5, 5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane. tert-butyl 5-(l-(tert- butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(l-methyl-6-oxo-5-vinyl-l,6- dihydropyridin-3-yl)-lH-indole-l-carboxylate (85.3 mg, 0.126 mmol, 72% yield, 85% purity) was obtained as a clear, pale yellow oil. LCMS MH+: 576.3. HPLC Ret. Time
I.24 min. Method Bl. ¾ NMR (400 MHz, CHLOROFORM-d) δ 8.19 (d, J=8.7 Hz, IH), 7.54 (d, J=1.5 Hz, IH), 7.38 (d, J=2.3 Hz, IH), 7.24-7.19 (m, 2H), 6.89 (dd, J=17.7,
I I.4 Hz, IH), 6.06 (dd, J=17.7, 1.5 Hz, IH), 5.39 (dd, J=11.2, 1.3 Hz, IH), 4.35-4.26 (m, 2H), 3.65 (s, 3H), 3.00 (dquin, J=14.2, 7.1 Hz, IH), 2.86 (t, J=12.2 Hz, 2H), 2.81-2.74 (m, IH), 1.90 (d, J=12.3 Hz, 2H), 1.71 (qd, J=12.5, 3.5 Hz, 2H), 1.51 (s, 9H), 1.40 (s, 9H), 1.38 (d, J=7.2 Hz, 6H). Example 67:
5% Pd on carbon (30 mg, 0.148 mmol) was weighed into a 2-dram vial, tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(l-methyl-6-oxo-5-vinyl-l,6- dihydropyridin-3-yl)-lH-indole-l-carboxylate (85.3 mg, 0.148 mmol) was dissolved in MeOH (1.482 mL) and transferred into the vial containing the Pd on C while under a nitrogen atmosphere. Ammonium formate (74.7 mg, 1.185 mmol) was added to the reaction mixture. The vial was placed under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered through celite, flushing with MeOH. Excess solvent was evaporated from the reaction mixture.
The resulting residue was partitioned between DCM and water (1: 1, 5 mL total volume), the phases were separated, and the aqueous phase was extracted with DCM (2x1 mL). Excess solvent was evaporated from the combined organic phases. The resulting residue was taken up in DCM and purified by flash chromatography on a 4 g silica column, eluting with ethyl acetate and hexanes to afford tert-butyl 5-(l-(tert- butoxycarbonyl)piperidin-4-yl)-2-(5-ethyl-l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indole-l-carboxylate (50.4 mg, 0.079 mmol, 53.0% yield) as a white solid. This was Boc-deprotected by reacting with 2: 1 trifluoroacetic acid/dichloromethane (1.2 mL, 0.044 mmol) in a 1-dram vial for 50 min. Toluene (~0.15 mL) was added, and excess solvent was then evaporated from the reaction. DMF (- 1.5 mL) was added to the resulting residue, and the crude material was purified via preparative LC/MS. Fractions containing the product were combined and dried via centrifugal evaporation to afford 3- ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (4.0 mg, 10.6 μιηοΐ, 24% yield, 100% purity). LCMS MH+: 378.1. HPLC Ret. Time 1.15 min. Method QC-ACN-TFA-XB. ¾ NMR (500 MHz, DMSO-de) δ 10.81 (s, 1H), 7.65 (s, 1H), 7.47 (s, 1H), 7.37 (br. s., 1H), 7.24 (d, J=8.2 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 3.53 (s, 2H), 3.47 (br. s., 1H), 3.20-3.08 (m, 3H), 2.71 (d, J=10.7 Hz, 3H), 1.82 (br. s., 3H), 1.78 (br. s., 2H), 1.67 (d, J=12.2 Hz, 2H), 1.39 (d, J=6.7 Hz, 6H), 1.14 (t, J=7.5 Hz, 3H).
EXAMPLE 68
l,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)pyridin-2(lH)-
Figure imgf000097_0001
Intermediate 68A: tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-l- ethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l-carboxylate
Figure imgf000097_0002
5-bromo-3-chloro-l-ethylpyridin-2(lH)-one (F-28) 0.058 g, 0.246 mmol) was coupled to tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-l-carboxylate (0.140 g, 0.246 mmol) as described above for Example 2. Obtained tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin- 4-yl)-2-(5-chloro-l-ethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l- carboxylate (120.6 mg, 0.192 mmol, 78% yield) as a yellow foam. LCMS MH+: 598.2. HPLC Ret. Time 1.24 min. Method Bl. ¾ NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, IH), 8.19 (s, IH), 7.61 (d, J=2.6 Hz, IH), 7.54 (d, J=1.6 Hz, IH), 7.48 (d, J=2.3 Hz, IH), 7.39 (d, J=2.6 Hz, IH), 7.23 (dd, J=8.7, 1.7 Hz, IH), 7.18 (d, J=2.3 Hz, IH), 4.30 (d, J=9.7 Hz, 2H), 4.14 (quin, J=6.9 Hz, IH), 4.05 (q, J=7.2 Hz, IH), 2.99 (quin, J=7.2 Hz, IH), 2.87 (t, J=12.3 Hz, 2H), 2.79 (tt, J=12.1, 3.4 Hz, IH), 1.91 (d, J=12.3 Hz, 2H), 1.72 (qd, J=12.3, 3.8 Hz, 2H), 1.54-1.51 (m, 9H), 1.45 (s, 9H), 1.43-1.40 (m, 2H), 1.39 (d, J=7.1 Hz, 6H).
Intermediate 68B: tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(l-ethyl-6-oxo- 5-vinyl-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l-carboxylate
Figure imgf000098_0001
tert-Butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-l -ethyl-6-oxo- l ,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l -carboxylate (45 mg, 0.075 mmol) was coupled to 4,4,5, 5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (31.9 μΐ, 0.188 mmol) as according to the general procedure for Intermediate 66B. Obtained tert-butyl 5-(l-(tert- butoxycarbonyl) piperidin-4-yl)-2-(l -ethyl-6-oxo-5-vinyl-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indole-l-carboxylate (43.6 mg, 0.055 mmol, 73.7% yield) as a pale yellow oil. LCMS MH+: 590.3. HPLC Ret. Time 1.26 min. Method Bl . Example 68:
tert-Butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(l -ethyl-6-oxo-5-vinyl-l ,6- dihydropyridin-3-yl)-3-isopropyl-lH-indole-l-carboxylate (26 mg, 0.044 mmol) was reduced and deprotected according to the general procedure for Example 66. Obtained l ,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)pyridin-2(lH)-one (4.0 mg, 9.81 μηιοΐ, 22% yield, 96% purity). LCMS MH+: 392.1. HPLC Ret. Time 1.34 min. QC- ACN-TFA-XB. ¾ NMR (500 MHz, DMSO-de) δ 10.84 (s, 1H), 7.71-7.60 (m, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.02 (q, J=6.9 Hz, 2H), 3.15 (dd, J=14.4, 7.2 Hz, 2H), 2.70 (br. s., 2H), 1.84 (br. s., 4H), 1.76 (br. s., 2H), 1.68 (br. s., 2H), 1.41 (d, J=7.0 Hz, 6H), 1.28 (t, J=7.1 Hz, 3H), 1.15 (t, J=7.4 Hz, 3H).
EXAMPLE 69
5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l -methyl-3-(pyrrolidine-l -carbonyl) pyridin-2(lH)-one
Figure imgf000099_0001
Intermediate 69A: Methyl 5-(5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-lH- indol-2-y 1)- 1 -met -2-oxo- 1 ,2-dihy dropy ridine-3-carboxy late
Figure imgf000099_0002
Methyl 5-bromo-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate (111 mg,
0.451 mmol) and tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indol-5-yl)piperidine-l-carboxylate (176 mg, 0.376 mmol) were coupled according to the general procedure for Example 1. Obtained methyl 5-(5-(l-(tert- butoxycarbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-methyl-2-oxo-l,2- dihydropyridine-3-carboxylate (141.1 mg, 0.250 mmol, 66.6% yield) as an orange solid. LCMS MH+: 508.3. HPLC Ret. Time 1.04 min. Method Bl. ¾ NMR (400 MHz, CHLOROFORM-d) δ 8.38 (s, IH), 8.24 (d, J=2.7 Hz, IH), 7.63 (d, J=2.7 Hz, IH), 7.59 (s, IH), 7.36 (d, J=8.4 Hz, IH), 7.09 (dd, J=8.4, 1.6 Hz, IH), 4.38-4.22 (m, 2H), 3.88 (s, 3H), 3.67 (s, 3H), 3.14 (spt, J=7.0 Hz, IH), 2.87 (t, J=12.3 Hz, 2H), 2.77 (tt, J=12.1, 3.4 Hz, IH), 1.96-1.87 (m, 2H), 1.73 (qd, J=12.6, 3.8 Hz, 2H), 1.52 (s, 9H), 1.47 (d, J=7.1 Hz, 6H).
Intermediate 69B: 5-(5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2- yl)-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylic acid
Figure imgf000099_0003
(69B) Methyl 5-(5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)- l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate (50 mg, 0.098 mmol) was suspended in MeOH (1 mL) in a 1-dram vial. Sodium hydroxide (0.197 mL, 0.197 mmol) was added to the vial, and the vial was capped. The reaction mixture was stirred at 65 °C for 1.5 h. Water (0.5 mL), IN aqueous HC1 (210 μί), ethyl acetate (1.5 mL) and brine solution (0.5 mL) were added to the reaction mixture, resulting in dissolution of the solid and formation of 2 layers (a colorless aqueous layer and a yellow organic layer). The phases were separated, and the aqueous layer was extracted with ethyl acetate (2x2 mL). The combined organic extracts were dried over sodium sulfate, then filtered, and excess solvent was evaporated off to afford 5-(5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylic acid (50.3 mg, 0.097 mmol, 98% yield) as a yellow solid. LCMS MH+: 494.4. HPLC Ret. Time 1.06 min. Method Bl . Example 69:
PyBOP (19.45 mg, 0.037 mmol), DIEA (10.88 μΐ, 0.062 mmol), and 5-(5-(l-(tert- butoxycarbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-methyl-2-oxo-l,2- dihydropyridine-3-carboxylic acid (12.3 mg, 0.025 mmol) were combined in DMF (500 μί) in a 1-dram vial and stirred for 10 min. Pyrrolidine (5.20 μΐ, 0.062 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between water and ethyl acetate (3 mL total volume), separated, and the aqueous phase was extracted with additional ethyl acetate (2x1 mL). Excess solvent was evaporated from the combined organic extracts. The resulting residue was deprotected with 2: 1 trifluoroacetic acid/dichloromethane (1.2 mL, 0.025 mmol) for 45 min. Excess solvent was evaporated from the reaction mixture. The crude material was dissolved in DMF (1.5 mL) and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-im particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge CI 8, 19 x 200 mm, 5-im particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifiuoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifiuoroacetic acid; Gradient: 7- 47% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 5- (3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrrolidine-l- carbonyl)pyridin-2(lH)-one (7.5 mg, 66% yield, 99% purity). LCMS MH+: 447.2.
HPLC Ret. Time 1.13 min. Method QC-ACN-TFA-XB. ¾ NMR (500 MHz, DMSO-de) δ 10.76 (s, 1H), 7.71 (s, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.31 (s, 1H), 7.09 (d, J=4.5 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 3.39 (br. s., 3H), 3.26-3.15 (m, 3H), 3.14-3.09 (m, 2H), 3.01-2.91 (m, 1H), 2.88-2.78 (m, 2H), 2.70 (s, 2H), 1.82-1.73 (m, 2H), 1.69-1.57 (m, 7H), 1.20 (d, J=7.0 Hz, 6H).
EXAMPLE 70
-(hydroxymethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-
Figure imgf000101_0001
Intermediate 70A: 5-bromo-3-(hydroxymethyl)pyridin-2(lH)-one
Figure imgf000101_0002
Methyl 5-bromo-2-oxo-l,2-dihydropyridine-3-carboxylate (Combi-Blocks, CAS: 120034-05-1, 0.100 g, 0.431 mmol) was dissolved in THF (4.31 mL) and added dropwise to a 0 °C solution of lithium aluminum hydride (0.082 g, 2.155 mmol) in THF (4.31 mL).
The reaction mixture was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for 2.5 h. Saturated aqueous NH4CI solution (8 mL) was slowly added to the reaction mixture, followed by ethyl acetate (8 mL). The phases were separated, the aqueous phase was extracted with additional ethyl acetate (2x10 mL). The combined organic phases were dried over sodium sulfate and filtered, and excess solvent was evaporated off to afford 5-bromo-3-(hydroxymethyl)pyridin-2(lH)-one (34.1 mg, 0.159 mmol, 36.8% yield) as a white solid. LCMS MH+: 203.9. HPLC Ret. Time 0.47 min. Method Bl . ¾ NMR (400 MHz, METHANOLS) δ 7.67 (dt, J=2.7, 1.4 Hz, 1H), 7.51 (d, J=2.7 Hz, 1H), 4.49 (s, 2H). Intermediate 70B: 5-bromo-3-(hydroxymethyl)-l-methylpyridin-2(lH)-one
Figure imgf000102_0001
(F-50)
5-bromo-3-(hydroxymethyl)pyridin-2(lH)-one (34.1 mg, 0.167 mmol) was stirred with iodomethane (30.5 μΐ, 0.201 mmol) and potassium carbonate (115 mg, 0.836 mmol) in DMF (557 μΐ) in a 2-dram vial containing a Teflon-coated stir bar at room temperature for 1 h. Additional DMF (1.0 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 19 h. The reaction mixture was partitioned between water and ethyl acetate (~4 mL total volume), and the aqueous phase was extracted with ethyl acetate (3x2.5 mL). The combined organic phases were extracted with brine (2x2 mL), then dried over sodium sulfate and filtered. Excess solvent was evaporated from the filtered organic phase to afford 5-bromo-3-(hydroxymethyl)-l- methylpyridin-2(lH)-one (17.7 mg, 0.073 mmol, 43.7% yield) as a clear, pale yellow oil. LCMS MH+: 217.9. HPLC Ret. Time 0.51 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.42 (s, 2H), 4.57 (d, J=6.2 Hz, 2H), 3.56 (s, 3H), 3.41 (t, J=6.4 Hz, 1H).
Example 70:
5-bromo-3-(hydroxymethyl)-l-methylpyridin-2(lH)-one was coupled to tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indol-5-yl)piperidine- 1-carboxylate and deprotected according to the general procedure for Example 1 to afford 3-(hydroxymethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-
2(lH)-one (21.9 mg, 70% yield, 98% purity). LCMS MH+: 380.4. HPLC Ret. Time 0.82 min. Method QC-ACN-TFA-XB. ¾ NMR (500 MHz, DMSO-de) δ 10.71 (s, 1H), 7.51 (s, 1H), 7.40 (br. s., 1H), 7.31 (s, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 4.21 (s, 2H), 3.55 (br. s., 4H), 3.36 (s, 2H), 3.1 1 (d, J=10.3 Hz, 1H), 2.99 (quin, J=6.9 Hz, 1H), 2.72 (d, J=11.2 Hz, 2H), 2.64 (br. s., 1H), 1.75-1.68 (m, 2H), 1.67-1.56 (m, 2H), 1.20 (d, J=6.9 Hz, 6H).
EXAMPLE 71
2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl) piperidin-l-yl)-N,N-dimethylacetamide
Figure imgf000103_0001
Method A: A mixture containing 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (75 mg, 0.206 mmol), 2-chloro-N,N-dimethylacetamide (0.027 mL, 0.258 mmol) and K2CO3 (86 mg, 0.619 mmol) was suspended in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was treated with water (4 mL) and stirred for 30 min. The resulting solids were filtered and rinsed with water and diethylether, and dried to afford 2-(4-(2-(l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N- dimethylacetamide (70 mg, 0.148 mmol, 71.8% yield), as a white solid, m/e (449, M+1). LCMS MH+: 449.5. HPLC Ret. Time 0.64 min. Method Bl. ¾ NMR (400 MHz, DMSO-de) δ 10.77 (s, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.48 (s, 1H), 7.45-7.40 (m, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.96 (dd, J=8.4, 1.4 Hz, 1H), 3.54 (s, 3H), 3.21-3.11 (m, 3H), 3.08 (s, 3H), 2.95 (d, J=l l. l Hz, 2H), 2.83 (s, 3H), 2.23-2.12 (m, 2H), 2.09 (s, 3H), 1.84-1.63 (m, 4H), 1.40 (d, J=7.0 Hz, 6H).
The following examples were prepared according to the general procedure for Example 71 using the indicated starting material. TABLE 4
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
EXAMPLE 171
5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin- -one
Figure imgf000120_0002
General Method 1: A mixture containing 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l,3-dimethylpyridin-2(lH)-one (100 mg, 0.275 mmol), oxetan-3-one (99 mg, 1.376 mmol) and sodium triacetoxyborohydride (233 mg, 1.100 mmol) was suspended in DMF (1 mL) followed by the addition of acetic acid (0.025 mL, 0.437 mmol). The reaction mixture was stirred for 20 h. The reaction mixture was treated with concentrated aqueous ammonium hydroxide (7 mL) and the resulting solids were stirred and sonicated periodically for 30 min. The resulting suspension was filtered, rinsed with additional ammonium hydroxide and dried to afford 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4- yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (55 mg, 0.125 mmol, 45.3 % yield), -95% pure, m/z (420, M+1). LCMS MH+: 420.2. HPLC Ret. Time 0.61 min. Method B. ¾ NMR (400 MHz, METHANOLS) δ 7.63 (d, J=2.3 Hz, 1H), 7.58 (s, 2H), 7.28 (d, J=8.3 Hz, IH), 7.03 (dd, J=8.4, 1.5 Hz, IH), 4.77-4.71 (m, 2H), 4.71-4.66 (m, 2H), 3.68 (s, 3H), 3.58 (quin, J=6.5 Hz, IH), 3.26-3.19 (m, IH), 2.96 (d, J=11.4 Hz, 2H), 2.65 (td, J=10.4, 5.3 Hz, IH), 2.22 (s, 3H), 2.10-2.01 (m, 2H), 1.97-1.86 (m, 4H), 1.48 (d, J=7.0 Hz, 6H).
EXAMPLE 172
5-(3-isopropyl-5-(l-(2-(methylamino)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l - methylpyridin-2(lH)-one
Figure imgf000121_0001
(172) General Method 2: To a solution containing 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l-methylpyridin-2(lH)-one, HC1 (30 mg, 0.078 mmol), Example 1, and tert-butyl methyl(2-oxoethyl)carbamate (26.9 mg, 0.155 mmol) in THF (1 mL) was added TEA (10.83 μΐ, 0.078 mmol) followed by the addition of sodium triacetoxyborohydride (65.9 mg, 0.31 1 mmol) and a drop of acetic acid. The reaction mixture was stirred for 20 h, diluted with ethyl acetate (5 mL) and washed with aqueous IN NaOH (2X2 mL) and saturated aqueous NaCl solution (lxl mL), filtered through a plug of Na2S04 and concentrated. The residue was dissolved in DCM (1 mL) and treated with TFA (0.5 mL). The reaction mixture was concentrated. The sample was dissolved in DMF (2 mL), filtered through an Acrodisc, 13 mm, 0.45 micron nylon membrane syringe filter. The crude material was purified via preparative LC/MS. Fractions containing the product were combined and dried via centrifugal evaporation to afford 5-(3-isopropyl-5-(l -(2- (methylaiTiino)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (18.5 mg, 0.046 mmol, 58.5% yield). LCMS MH+: 407. HPLC Ret. Time 0.79 min. Method B. ¾ NMR (500 MHz, DMSO-de) δ 10.83 (s, IH), 7.81 (d, J=2.1 Hz, IH), 7.54 (dd, J=9.3, 2.3 Hz, IH), 7.50-7.45 (m, IH), 7.26-7.21 (m, IH), 6.99-6.94 (m, IH), 6.56-6.49 (m, IH), 3.20-3.10 (m, IH), 2.98 (br d, J=10.9 Hz, 2H), 2.77-2.72 (m, 2H), 2.55 (s, 3H), 2.47 (br t, J=6.2 Hz, 2H), 2.40 (s, 3H), 2.06 (br t, J=10.5 Hz, 2H), 1.87 (s, IH), 1.81 -1.67 (m, 4H), 1.40 (d, J=7.0 Hz, 6H). EXAMPLE 173
5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(piperidin- -2(lH)-one
Figure imgf000122_0001
A mixture of tert-butyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-l- methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indole-l-carboxylate (20 mg, 0.034 mmol), piperidine (10.15 μΐ, 0.103 mmol), Xantphos (2.97 mg, 5.14 μηιοΐ), Pd2(dba)3 (2.351 mg, 2.57 μιηοΐ), and Cs2C03 (44.6 mg, 0.137 mmol) in dioxane (1.0 mL) was purged with nitrogen for 2 min. and then stirred at 130 °C. The reaction mixture was cooled to room temperature and checked by LCMS. The product m/z (633.3, M+H) was observed. The reaction mixture was partitioned between water and ethyl acetate (1 : 1, 3 mL total volume), and the phases were separated. The aqueous phase was extracted with ethyl acetate (2x1 mL), and excess solvent was evaporated from the combined organic phases. The resulting residue was Boc-deprotected with 2: 1 trifluoroacetic acid/dichloromethane (1.2 mL, 0.034 mmol), stirring at room temperature for 30 min. Toluene (-150 μί) was added to the reaction mixture, and concentrated to dryness. The residue was taken up in DMF (-1.8 mL) and purified by preparative LCMS to afford 5- (3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(piperidin-l-yl) pyridin-2(lH)- one, TFA (12.3 mg, 0.011 mmol, 32.9% yield) as a greenish oil. DMF (225 μΐ) was added to 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(piperidin-l- yl)pyridin-2(lH)-one, TFA (12.3 mg, 0.023 mmol) in a 1-dram vial, followed by DIEA (9.82 μΐ, 0.056 mmol) and propionaldehyde (16.38 μΐ, 0.225 mmol). The reaction mixture was stirred at room temperature for 5 min, then acetic acid (7.73 μΐ, 0.135 mmol) and sodium triacetoxyborohydride (47.7 mg, 0.225 mmol) were added. The reaction mixture was stirred at room temperature for 2 h, diluted with MeOH (1 mL) and subjected to HPLC purification to afford 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)- l-methyl-3-(piperidin-l-yl)pyridin-2(lH)-one, (0.7 mg, 7%). LCMS MH+: 475. HPLC Ret. Time 1.76 min. Method QC-ACN-AA-XB.
The following examples were prepared according to the general procedures Examples 171-173, using the indicated starting material.
TABLE 5
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Isomer 2
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
EXAMPLE 271
5-(5-(l-(2-(dimethylainino)acetyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- -2(lH)-one
Figure imgf000139_0002
General Method C: A mixture containing 2-(dimethylamino)acetic acid (12.38 mg, 0.120 mmol), 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one, HCl (32 mg, 0.080 mmol), and HCTU (49.6 mg, 0.120 mmol) was suspended in THF (1 mL), followed by the addition of TEA (0.045 mL, 0.32 mmol). The reaction mixture was stirred for 7 h and concentrated to dryness under a stream of nitrogen. The residue was suspended in aqueous 0.1 N NaOH (5 mL) and stirred for 30 min. The solids were filtered, rinsed sequentially with additional 0.1 N NaOH and water, and dried to afford 5- (5-(l-(2-(dimethylamino)ace1yl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (35 mg, 0.074 mmol, 93% yield). LCMS MH+: 449.2. HPLC Ret. Time 0.67 min. Method Bl . ¾ NMR (400 MHz, CHLOROFORM-d) δ 7.91 -7.86 (m, 1H), 7.61 -7.57 (m, 1H), 7.36-7.30 (m, 2H), 7.06 (dd, J=8.4, 1.5 Hz, 1H), 4.81 (br d, J=13.5 Hz, 1H), 4.27 (br d, J=13.5 Hz, 1H), 3.64 (s, 3H), 3.26-3.13 (m, 1H), 2.93-2.84 (m, 1H), 2.84-2.80 (s, 2H), 2.76-2.67 (m, 1H), 2.35 (s, 6H, 2.24 (s, 3H), 1.99 (br m, J=12.7 Hz, 1H), 1.81-1.59 (m, 4H), 1.47 (d, J=7.0 Hz, 6H).
EXAMPLE 272
5-(5-(l -(l-aminocyclopropanecarbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one
Figure imgf000140_0001
A mixture containing l -((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (15.3 mg, 0.075 mmol), 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one, HC1 (20 mg, 0.050 mmol), and HCTU (31.0 mg, 0.075 mmol) was suspended in THF (0.5 mL) and TEA (0.035 mL, 0.250 mmol) was added. The reaction mixture was stirred for 20 h, diluted with ethyl acetate (4 mL) and washed with IN NaOH (2x1 mL) and saturated aqueous NaCl solution (1 mL) and concentrated. The residue was treated with TFA (1 mL) for 30 min to facilitate the removal of the Boc groups. The reaction mixture was re-concentrated to dryness and re-dissolved in DMF (2 mL). The sample was filtered through an Acrodisc, 13 mm, 0.45 micron nylon membrane syringe filter. The crude material was purified via preparative LC/MS. Fractions containing the product were combined and dried via centrifugal evaporation to afford 5- (5-(l -(l -aminocyclopropanecarbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (2.6 mg, 12%). LCMS MH+: 449.2. HPLC Ret. Time 1.21 min. Method- QC-ACN-AA-XB. ¾ NMR (500 MHz, DMSO-de) δ 10.79 (s, IH), 7.66- 7.59 (m, IH), 7.47 (s, IH), 7.43 (br s, IH), 7.23 (br d, J=8.3 Hz, IH), 6.95 (br d, J=8.2 Hz, IH), 4.44 (br d, J=12.5 Hz, 2H), 3.66-3.59 (m, 3H), 3.19-3.09 (m, 2H), 2.90-2.71 (m, 2H), 2.54 (s, IH), 2.07 (s, 3H), 1.86-1.75 (m, 3H), 1.69-1.48 (m, 2H), 1.37 (br d, J=6.8 Hz, 6H), 0.83 (br s, 2H), 0.67 (br s, 2H).
The following examples were prepared according to the general method for Examples 271 or Example 272, using the indicated starting material.
TABLE 6
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
EXAMPLE 309
3-chloro-5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)- -dimethylpyridin-2(lH)-one
Figure imgf000147_0002
General Method D: Tert-butyl 4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (25 mg, 0.050 mmol) was deprotected with 2: 1 trifluoroacetic acid/dichloromethane (1.2 mL, 0.050 mmol) for 45 min. Toluene (0.2 mL) was added to the reaction mixture and excess solvent was evaporated. The resulting residue was stirred with isobutylene oxide (0.023 mL, 0.251 mmol) and potassium carbonate (41.6 mg, 0.301 mmol) in methanol (0.502 mL) at room temperature for 19 h. The reaction mixture was partitioned between water and ethyl acetate (- 3.5 mL total volume). The phases were separated, and the aqueous phase was extracted with ethyl acetate (2x1 mL). The organic phases were combined and excess solvent was evaporated off. DMF (1 mL) was added to the resulting yellow residue, and the crude material was purified via preparative LC/MS. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of 3-chloro-5-(5-(l-(2- hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l ,4-dimethylpyridin- 2(lH)-one was 19.8 mg (82%), and its estimated purity by LCMS analysis was 98%. LCMS MH+: 470.3. HPLC Ret. Time 1.26 min. Method: QC-ACN-TFA-XB. ¾ NMR: (500 MHz, DMSO-de) δ 10.77 (s, IH), 7.71 (s, IH), 7.47 (s, IH), 7.22 (d, J=8.3 Hz, IH), 6.99 (d, J=8.2 Hz, IH), 3.05 (d, J=11.2 Hz, 2H), 2.90 (dt, J=14.0, 7.0 Hz, IH), 2.30-2.22 (m, 4H), 2.06 (s, 3H), 1.90 (s, 2H), 1.78-1.68 (m, 4H), 1.30 (d, J=6.5 Hz, 6H), 1.1 1 (s, 6H).
The following examples were prepared in a manner similar to Example 309, using the indicated starting material.
TABLE 7
Figure imgf000148_0001
Figure imgf000149_0001

Figure imgf000150_0001
Figure imgf000151_0001
The following examples were prepared according to the general procedures above examples. TABLE 8
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
The following example was prepared according to the general procedures of Examples 1 and 2 using the indicated fragment.
TABLE 9
Figure imgf000156_0002
BIOLOGICAL ASSAYS
The pharmacological properties of the compounds of this invention may be confirmed by a number of biological assays. The exemplified biological assays, which follow, have been carried out with compounds of the invention.
TLR7/8/9 Inhibition Reporter Assays
HEK-Blue™-cells (Invivogen) overexpressing human TLR7, TLR8 or TLR9 receptors were used for screening inhibitors of these receptors using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene under the control of the IFN-β minimal promoter fused to five NF-κΒ and AP-1 -binding sites. Briefly, cells are seeded into Greiner 384 well plates (15000 cells per well for TLR7, 20,000 for TLR8 and 25,000 for TLR9) and then treated with test compounds in DMSO to yield a final dose response concentration range of 0.05 nM - 50 μΜ. After a 30 minute compound pre-treatment at room temperature, the cells are then stimulated with a TLR7 ligand (gardiquimod at a final concentration of 7.5 μΜ), TLR8 ligand (R848 at a final concentration of 15.9 μΜ) or TLR9 ligand (ODN2006 at a final concentration of 5 nM) to activate NF-κΒ and AP-1 which induce the production of SEAP. After a 22 hour incubation at 37 °C, 5% CC , SEAP levels are determined with the addition of HEK-Blue™ Detection reagent (Invivogen), a cell culture medium that allows for detection of SEAP, according to manufacturer's specifications. The percent inhibition is determined as the % reduction in the HEK-Blue signal present in wells treated with agonist plus DMSO alone compared to wells treated with a known inhibitor.
TABLE 10
TLR7/8/9 Inhibition Data
Figure imgf000157_0001
TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
14 3.5 3.6 1652
15 1.9 3.3 179
16 301.9 172.7 914
17 21.1 12.2 597
18 18.3 14.7 6653
19 25.7 39.7 792
20 6.0 17.0 1786
21 104.9 263.2 6540
22 1.1 10.7 2549
23 62.8 15.1 6265
24 75.9 10.7 3757
25 40.3 7.8 1372
26 12.0 8.9 1859
27 164.8 18.5 -
28 206.6 173.7 1206
29 14.1 50.9 783
30 8.4 10.1 2386
31 1.0 7.0 1121
32 1.8 17.2 1068
33 16.1 12.6 922
34 7.1 48.0 1463
35 60.0 6.8 574
36 9.6 81.2 1311
37 458.1 182.2 2432
38 51.2 30.3 3033
39 7.9 7.9 3181
40 5.2 16.9 4448
41 18.0 157.6 1120
42 40.9 134.1 6706 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
43 1 10.4 156.6 1562
44 3.8 19.4 2083
45 12.9 48.4 4667
46 2.9 29.9 919
47 31.9 41.1 1885
48 13946.5 50000.0 1274
49 2614.0 2087.2 50000
50 6.8 7.7 41 1
51 10.9 30.6 2585
52 184.6 141.6 1521
53 1 1.4 10.3 -
54 23.4 5.9 753
55 13.9 202.8 2289
56 13.7 49.0 408
57 68.4 81.9 1357
58 5.4 222.3 3480
59 46.6 270.4 5848
60 90.3 210.9 3062
61 2193.6 2275.1 2083
62 3125.0 3125.0 50000
63 3125.0 3125.0 50000
64 479.7 1082.2 7378
65 975.5 75.1 3104
66 12.6 70.5 764
67 4.3 5.9 919
68 8.5 9.8 5359
69 333.1 179.5 50000
70 8.6 26.1 2449
71 2.8 5.1 1 1002 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
72 21.8 17.3 50000
73 8.0 3.3 6074
74 20.9 4.9 4327
75 5.0 5.6 9325
76 4.4 4.7 19915
77 123.2 50.6 7851
78 67.6 64.0 34764
79 1 1.1 10.8 3794
80 127.6 140.7 48780
81 8.8 20.3 50000
82 9.5 1 1.9 799
83 3.9 1.2 7140
84 44.3 73.6 50000
85 2.2 4.6 8455
86 2.1 4.6 2543
87 3.1 5.7 2563
88 67.5 53.2 -
89 16.9 4.5 1958
90 21.7 7.0 1973
91 2.6 5.0 4386
92 3.2 2.8 8512
93 5.0 4.9 5802
94 8.0 1.3 2033
95 7.0 7.8 6092
96 2.0 14.3 2861
97 5.2 9.7 2047
98 20.6 10.4 8752
99 7.1 10.3 4981
100 21.5 2.3 3055 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
101 12.8 9.3 4876
102 33.2 32.4 50000
103 9.6 1.3 2083
104 13.1 3.5 2699
105 5.1 10.7 5517
106 6.2 5.5 1248
107 6.6 4.4 13353
108 32.8 2.0 7542
109 13.0 9.7 5306
110 56.1 163.5 5258
11 1 48.0 157.5 3060
112 38.9 70.5 2363
113 26.4 70.7 2189
114 42.9 43.6 10375
115 48.0 42.1 6594
116 29.6 23.8 6099
117 2.0 5.3 13975
118 18.6 14.5 9636
119 1 1.4 14.9 1155
120 7.4 1 1.5 851
121 40.7 102.3 50000
122 4.9 15.7 14719
123 7.0 8.0 23803
124 9.7 1 1.3 50000
125 3125.0 288.7 50000
126 3125.0 631.4 50000
127 3.7 5.2 33623
128 3.0 5.7 977
129 5.0 8.0 2928 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
130 289.6 25.9 8506
131 244.6 33.4 16237
132 9.0 15.1 25521
133 24.1 6.2 14874
134 1 1.9 8.7 3461
135 5.3 5.6 18958
136 12.0 13.6 1954
137 19.9 12.3 1 1508
138 17.5 5.2 7613
139 15.4 4.2 10356
140 47.8 39.7 21905
141 27.9 37.3 4457
142 204.9 95.4 7649
143 413.2 99.7 2717
144 59.9 4.7 1 1388
145 63.8 10.7 7175
146 38.8 4.5 6992
147 56.3 4.8 5016
148 193.4 364.0 50000
149 16.0 27.3 23168
150 1.2 4.4 1 1377
151 1.2 13.7 1 1046
152 1.4 4.6 16580
153 3.5 12.6 7883
154 4.6 26.6 13839
155 5.3 24.2 21139
156 4.3 7.4 1 1792
157 12.8 12.2 6387
158 6.6 2.6 3525 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
159 10.2 19.7 16617
160 8.9 14.5 14739
161 50.5 239.5 8734
162 8.4 99.4 4120
163 12.3 117.6 3887
164 7.0 42.4 2555
165 45.8 113.4 10083
167 61.7 15.6 49253
168 7.9 10.3 2380
169 1 1.9 6.2 1800
170 19.8 14.4 2075
171 5.1 10.4 25229
172 29.9 6.9 151
173 3125.0 983.1 6611
174 15.7 44.8 50000
175 275.1 87.5 15517
176 1.3 1.3 177
177 154.5 51.9 9211
178 3.9 3.2 7087
179 95.1 28.8 3928
180 7.0 8.2 5745
181 2.0 8.5 13516
182 5.9 7.3 5547
183 28.5 31.4 9652
184 71.8 34.2 2124
185 61.3 19.0 4325
186 1 12.2 75.5 6730
187 85.4 30.1 655
188 14.1 1 1.1 526 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
189 25.5 25.0 47836
190 25.6 53.8 2265
191 6.9 21.5 8842
192 6.4 12.0 2824
193 12.6 1 1.7 8916
194 10.2 6.3 2979
195 3.9 2.6 5191
196 3.0 2.4 4978
197 4.6 2.4 8342
198 9.1 13.4 50000
199 1.9 4.2 1550
200 4.3 2.2 3739
201 4.0 4.4 959
202 1 1.3 13.5 5634
203 271.7 28.7 16865
204 14.6 18.0 50000
205 500.8 19.8 8709
206 18.9 2.6 4495
207 20.8 1 1.7 46799
208 31.1 7.0 3109
209 34.3 18.0 17495
210 24.7 2.7 5031
21 1 34.6 17.1 50000
212 17.1 17.4 12619
213 15.6 16.5 2906
214 13.9 7.9 5692
215 66.1 54.9 17176
217 659.5 162.8 10935
219 48.0 9.1 22305 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
220 24.5 1.4 2785
221 67.0 9.3 25379
222 15.6 0.9 3067
223 10.0 13.6 5907
224 1.8 4.5 14025
225 4.6 3.6 6989
226 3.8 7.0 10444
227 3.8 4.1 3037
228 3.6 4.3 4269
229 5.7 4.2 50000
230 1 1.2 23.1 5513
231 7.0 22.3 3227
232 2.9 1.1 6010
233 57.7 97.0 -
234 40.2 52.3 -
235 1 1.0 5.2 1767
236 4.6 9.8 980
237 181.1 19.8 2104
238 7.2 1 1.8 8334
239 5.4 5.3 5808
240 1.0 3.7 2588
241 8.3 4.8 4866
242 3.2 5.1 2680
243 1.4 9.1 1772
244 6.0 1.8 954
245 7.3 2.0 851
246 2.9 1.7 387
247 3.0 4.1 864
248 5.6 16.9 30048 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
249 14.1 1.1 1765
250 6.3 4.8 3006
251 3.5 8.1 3527
252 4.2 2.7 2657
253 6.1 5.2 1241
254 5.5 2.1 2666
255 4.8 2.3 1819
256 12.4 1.7 1473
257 15.6 1.1 1979
258 4.5 1.1 832
259 6.1 0.6 983
260 23.2 3.1 2237
261 8.8 7.1 3361
262 47.7 52.3 2121
263 10.8 24.1 1565
264 13.5 927.2 6088
265 20.1 42.6 5026
266 1 1.6 15.8 4481
267 2.2 6.6 3535
268 2.4 6.6 2626
269 35.5 4.6 5904
270 2.1 4.7 4159
271 5.3 8.3 13527
272 7.9 53.0 -
273 90.2 16.0 2078
274 183.3 15.3 1589
275 193.8 95.7 3194
276 52.2 80.2 4764
277 9.3 21.0 15626 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
278 5.3 21.0 3202
279 23.1 5.9 7059
280 6.1 9.0 4569
281 47.4 29.6 5697
282 5.2 7.0 6273
283 512.1 46.8 6246
284 6.5 21.8 1655
285 14.6 99.1 3414
286 5.0 5.6 289
287 7.8 8.6 18171
288 17.4 61.7 2498
289 5.9 12.3 5283
290 8.3 17.1 1085
291 12.3 1 1.2 1417
292 7.2 40.7 492
293 21.6 74.9 12500
294 12.5 16.9 3316
295 1 14.2 61.9 9687
296 1.1 3.0 4308
297 4.4 5.5 3994
298 168.6 147.7 21284
299 3.7 4.3 504
300 42.6 42.5 50000
301 25.7 36.5 1830
302 20.4 213.8 50000
303 9.6 49.9 50000
304 7.8 80.0 50000
305 1 1.0 97.5 50000
306 16.5 26.9 547 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
307 7.5 1 1.2 2748
308 2.0 22.1 5655
309 13.7 5.3 8509
310 2.3 1.3 5543
31 1 17.7 3.9 3145
312 35.1 22.2 3171
313 4.7 3.1 8036
314 5.2 5.1 10069
315 6.7 1.8 4938
316 10.2 1.9 3086
317 19.3 7.2 3585
318 360.6 22.3 3433
319 10.9 1.6 4328
320 14.2 1.7 2310
321 36.7 1.6 4370
322 45.7 1.0 4789
323 18.4 13.9 7177
324 2.5 2.8 1 1550
325 8.7 4.3 3002
326 6.1 0.6 1661
327 6.0 1.6 3279
328 49.1 54.7 5969
329 15.8 32.4 -
330 7.7 432.2 705
331 6.3 9.6 2713
332 4.9 1.1 789
333 92.2 1 1.1 3009
334 8.6 0.8 487
335 2.4 5.9 529 TLR7 TLR8 TLR9
Ex No.
IC50 (nM) IC50 (nM) IC50 (nM)
336 10.2 1.2 553
337 1.8 1 1.9 2492
338 1.1 13.5 772
339 28.9 2143.7 1023
340 4.5 16.6 1210
341 16.2 4.3 714
342 12.9 16.0 3333
343 18.3 14.2 1168
344 1 1.5 26.5 322
345 1 1.1 16.9 7048
346 37.9 86.8 16676
347 7.2 28.6 13597
348 7.1 25.3 10830
349 14.5 72.6 782
350 14.4 1.4 2139
351 78.5 134.6 1 1923
352 21.5 31.5 2416

Claims

1. A compound of Formula (I)
Figure imgf000170_0001
or a salt thereof, wherein:
Figure imgf000170_0002
Ri is H, CI, -CN, CM alkyl, C1-3 fluoroalkyl, C 1-3 hydroxy-fluoroalkyl, -CRZ=CH2, C3-6 cycloalkyl, -CH2(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), or tetrahydropyranyl;
R2 is Ci-6 alkyl, C1-3 fluoroalkyl, Ci-6 hydroxyalkyl, C 1-3 aminoalkyl, -(CH2)o-40(Ci-3 alkyl), C3-6 cycloalkyl, -(CH2)i-3C(0)NRxRx, -CH2(C3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl;
each R2a is independently H, halo, -CN, -NRXRX, Ci-6 alkyl, C 1-3 fluoroalkyl, C 1-3
hydroxyalkyl, C1-3 fluoroalkoxy, -(CH2)o-20(Ci-3 alkyl), -(CH2)o-3C(0)NRxRx, -(CH2)i-3(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), -C(0)NRx(Ci-3 alkyl),
Figure imgf000170_0003
Figure imgf000170_0004
cycloalkyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry;
each Ry is independently F, CI, -CN, C 1-3 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy,
-NRxC(0)(Ci-3 alkyl), -C(0)NRxRx, C3-6 cycloalkyl, piperidinyl, or mo holinyl; R2b is R2 or R2a;
R2c is R2 or R2a; provided that one of R2b and R2c is R2, and the other of R2b and R2c is R2a; R3 is
(a) -Li-A; or
(b) H, Ci-6 alkyl, Ci-6 fluoroalkyl, Ci-6 hydroxyalkyl, C1-3 cyanoalkyl, -(CH2)o-40(Ci-3 alkyl), -(CH2CH20)2-30(Ci-3 alkyl), -CH2CH2NRXRX, -CRxRxC(0)OH, -(CRxRx)o-2C(0)NRxRx, -CH2C(0)NRx(Ci-3 alkyl), -CH2C(0)NRx(Ci-4
hydroxyalkyl), -(CRxRx)o-2S(0)2(Ci-3 alkyl), -C(0)(Ci-3 alkyl), -C(0)(Ci-3
fluoroalkyl), -C(0)CRxRxNRxRx, -C(0)(Ci-e hydroxyalkyl), or -NRxC(0)(Ci-3 alkyl);
Li is a bond, -(CRxRx)i-2- -(CRxRx)i-2CRx(OH)-, -(CRxRx)i-20-, -CRxRxC(0)-,
-(CRxRx)2NRx(CRxRx)o-i-, -CRxRxC(0)NRx(CRxRx)o-4-, -C(0)(CRxRx)o-3- -C(0)(CRxRx)o-2NRx(CRxRx)o-2-, -C(0)(CRxRx)o-2NRx(CRxRx)i-2CRx(OH)-, -C(0)(CRxRx)i-2C(0)NRx-, -(CRxRx)o-2C(0)NRx(CRxRx)i-2CRx(OH)-,
-C(0)(CRxRx)o-iO- -C(0)(CRxRx)i-2NHS(0)2-, -C(0)NRx(CRxRx)i-2- or
-S(0)2(CRxRx)o-2-;
A is adamantanyl, azepanyl, azetidinyl, C3-6 cycloalkyl, diazepanyl, dihydroinonyl,
dihydropyrimidinonyl, dioxidoisothiazolidinyl, dioxidothiazinanyl,
dioxotetrahydrothiophenyl, dioxotetrahydrothiopyranyl, dioxothiomo holinyl, furanyl, imidazolyl, imidazolidinonyl, indolyl, isoquinolinyl, isoxazolyl, morpholinyl, mo holinonyl, naphthalenyl, oxazolidinonyl, oxadiazolyl, oxetanyl, oxazolyl, phenyl, piperidinyl, piperidinonyl, piperazinyl, piperazinonyl, pyrazinyl, pyrazolyl, pyrazolidinonyl, pyridazinonyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl, pyrrolyl, quinolinyl, quinolizinonyl, tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, or triazolyl, each substituted with zero, 1, or 2 R3a;
each R3a is independently F, CI, -OH, -NH2, C1-3 alkyl, C1-2 fluoroalkyl, or -C(0)NRxRx; each R4 is independently F, -OH, Ci-2 alkyl, or -OCH3; or two R4 attached to the same carbon atom form =0;
each R5 is independently F, CI, -CN, Ci-2 alkyl, Ci-2 fluoroalkyl, or -OCH3;
each Rx is independently H or -CH3;
Rz is H, Ci-2 alkyl, or Ci-2 fluoroalkyl;
m is zero, 1, 2, 3, or 4; and
n is zero, 1, 2, or 3.
2. The compound according to claim 1 or a salt thereof, wherein:
Ri is H, Ci-4 alkyl, Ci-3 fluoroalkyl, or C3-6 cycloalkyl; R.2 is Ci-4 alkyl, C1-2 fluoroalkyl, C1-4 hydroxyalkyl, -(CH2)i-30CH3, C3-6 cycloalkyl, -CH2C(0)NRxRx, -CH2(C3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, or phenyl;
each R2a is independently H, F, CI, -CN, -NRXRX, Ci-6 alkyl, C1-2 fluoroalkyl, C1-3
hydroxyalkyl, -(CH2)o-20(Ci-2 alkyl), -(CH2)o-2C(0)NRxRx, -(CH2)i_3(cyclopropyl), -C(0)0(Ci-2 alkyl), -C(0)NRx(Ci-3 alkyl), -CRX=CH2, -CH=CH(C3-e cycloalkyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry;
each Ry is independently F, CI, -CN, C1-2 alkyl, C1-2 alkoxy, -NRxC(0)(Ci-2 alkyl), -C(0)NRxRx, C3-6 cycloalkyl, or morpholinyl;
R3 is
(a) -Li-A; or
(b) H, Ci-6 alkyl, Ci-6 fluoroalkyl, Ci-6 hydroxyalkyl, Ci-3 cyanoalkyl, -(CH2)o-30(Ci-2 alkyl), -(CH2CH20)2-30(Ci-2 alkyl), -CH2CH2NRXRX, -CRxRxC(0)OH,
-(CRxRx)o-2C(0)NRxRx, -CH2C(0)NRx(Ci-2 alkyl), -CH2C(0)NH(Ci-4
hydroxyalkyl), -(CRxRx)i_2S(0)2(Ci-2 alkyl), -C(0)(Ci-2 alkyl), -C(0)(Ci-2
fluoroalkyl), -C(0)CRxRxNRxRx, -C(0)(Ci-4 hydroxyalkyl), or -NRxC(0)(Ci-2 alkyl);
Li is a bond, -(CRxRx)i-2- -CRxRxC(0)-, -C(0)(CRxRx)o-i-, -C(0)0- or
-S(0)2(CRxRx)o-2-;
A is azetidinyl, C3-6 cycloalkyl, dioxotetrahydrothiophenyl, oxetanyl, phenyl, piperidinyl,, pyrazolyl, pyrazolidinonyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, or triazolyl, each substituted with zero, 1, or 2 R3a;
each R3a is independently F, CI, -OH, -NH2, C1-3 alkyl, C1-2 fluoroalkyl, or -C(0)NRxRx; each R4 is independently F, -OH, -CH3, or -OCH3; or two R4 attached to the same
carbon atom form =0;
each R5 is independently F, -CN, -CH3, -CF3, or -OCH3; and
Figure imgf000172_0001
3. The compound according to claim 1 or a salt thereof, wherein: Ri is -CH2CH3 or -CH(CH3)2;
R2 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)2OH, -CH2CHF2, -CH2CF3, -CH2CH2OCH3, -CH2(cyclopropyl), -CH2(phenyl), -CH2C(0)NH2, tetrahydrofuranyl, or phenyl;
each R2a is independently H, F, CI, -CN, -NH2, C1-5 alkyl, -CF3, -CH2OH, -OCH3, -CH2OCH3, -CH2CH2(cyclopropyl), -C(0)OCH3, -C(0)N(CH3)2,
-C(0)NH(CH2CH2CH3), -CH=CH2, -C(CH3)=CH2, -CH=CH(cyclopropyl), -C(0)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 Ry;
each Ry is independently F, -CN, -CH3, -CF3, -OCH3, -NHC(0)CH3, -C(0)NH2,
-C(0)NH(CH3), cyclopropyl, or morpholinyl;
Ra> is R2 or R2a;
R2c is R2 or R2a; provided that one of Ra> and R2c is R2, and the other of Ra and R2c is R2a;
R3 is H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2,
-CH2CH2CH(CH3)2, -CH2CH2CF3, -CH2CH2CH2CF3, -CH2CH2CH(CF3)2,
-CH2CH2OH, -CH2CH2CH2OH, -C(CH3)2OH, -CH2C(CH3)2OH,
-CH2CH2C(CH3)2OH, -CH2CH(OH)CH(CH3)2, -CH2CH(OH)CH2OH,
-CH(CH2CH2OH)2, -CH2CN, -CH2CH2CN, -CH2CH2OCH3, -CH2CH2CH2OCH3, - (CH2CH20)2-3OCH3, -CH2CH2NH(CH3), -C(CH3)2C(0)OH, -CH2C(0)NH2, -CH2C(0)NH(CH3), -CH2C(0)N(CH3)2, -CH2C(0)NH(CH2CH3),
-CH2C(0)NH(CH2CH(CH3)OH), -CH2C(0)NH(CH2C(CH3)2OH),
-CH(CH3)C(0)NH2, -C(CH3)2C(0)NH2, -CH2CH2C(0)NH2, -CH2CH2S(0)2CH3, -C(0)CH3, -C(0)CF3, -C(0)CH2N(CH3)2, -C(0)C(CH3)2NH2,
-C(0)CH(CH3)NH(CH3), -C(0)C(CH3)2NH(CH3), -C(0)CH2CH(CH3)OH, -C(0)CH2C(CH3)2OH, -C(0)C(CH3)2CH2OH, -NHC(0)CH3, -CH2(methyl triazolyl), -CH2(trifluoromethyl phenyl), -CH2(difluoromethyl, fluorophenyl), -CH2(fluoro, chlorophenyl), -CH2(difluorocyclopropyl), -CH2CH2(pyrrolidin- dionyl), -CH2(oxetanyl), -CH2(tetrahydropyranyl), -CH2C(0)(hydroxypyrrolidinyl), -CH2C(0)(pyrazolidinonyl), -CH2C(0)(pyrrolidinyl), -CH2(dimethyl pyrazolyl), -CH2(methyl pyrazolyl), -CH2(pyrazolyl), -CH2(cyclopropyl), -CH2(tetrahydrofuranyl), -CH2(/'-propyl pyrazolyl), -CH2(«-propyl pyrazolyl), -CH(CH3)(methyl pyrazolyl), -C(0)(aminocyclopropyl),
-C(0)(hydroxypyrrolidinyl), -C(0)(methyl, hydroxypyrrolidinyl),
-C(0)CH2(pyrrolidinonyl), -C(0)CH2(pyrrolidinyl), -C(0)0(methyl pyrrolidinyl), -S(0)2CH2CH2(pyrrolidinyl), -CH2(hydroxytetrahydropyranyl), or a cyclic group selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, piperidinyl, and dioxotetrahydrothiophenyl, each substituted with zero, 1, or 2 R3a;
each R3a is independently F, -OH, -CH3, -CH(CH3)2, -CF3, or -C(0)NH2;
R5 is F;
m is zero; and
n is zero or 1.
4. The compound according to claim 1 or a salt thereof, wherein
Figure imgf000174_0001
5. The compound according to claim 1 or a salt thereof, wherein
Figure imgf000174_0002
6. The compound according to claim 1 or a salt thereof, wherein said compound is selected from 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-on (1); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (2); 5 -(3 -isopropy 1-5 -(piperidin-4-y 1)- 1 H-indol-2-y 1)- 1 ,3 ,6-trimethy lpyridin-2( lH)-one (3);5 - (3-isopropy 1-5 -(piperidin-4-yl)- 1 H-indol-2-y 1)- 1 ,6-dimethy lpy ridin-2(l H)-one (6); 5 -(3 - isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (8); 3-amino- 5 -(3 -isopropy 1-5 -(piperidin-4-y 1)- lH-indol-2-y 1)- 1 -methy lpy ridin-2( 1 H)-one (9); 3 - fluoro-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (13); 5 -(3 -isopropy 1-5 -(piperidin-4-y 1)- 1 H-indol-2-y 1)- 1 ,3 ,4-trimethy lpyridin-2( 1 H)-one (14); l-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (15);
1- isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)pyridin-2(lH)-one (16); 3- amino-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (19); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l-methylpyridin- 2(lH)-one (20); 3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methylpyridin-2(lH)-one (22); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,6- dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (23); 5-(3-isopropyl-5-(piperidin-4- yl)-lH-indol-2-yl)-l,4-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (24); 3-ethyl-5- (3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,6-dimethylpyridin-2(lH)-one (25); 1- ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3,4-dimethylpyridin-2(lH)-one (26); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l,6-dimethylpyridin- 2(lH)-one (28); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l,4- dimethylpyridin-2(lH)-one (29); 1 -(2 -hydroxy ethyl)-5-(3-isopropyl-5-(piperidin-4-yl)- lH-indol-2-yl)-3-methylpyridin-2(lH)-one (30); 3-chloro-5-(3-isopropyl-5-(piperidin-4- yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (31); 3-chloro-l-ethyl-5-(3-isopropyl- 5-(piperidin-4-yl)-lH-indol-2-yl)pyridin-2(lH)-one (32); 3-chloro-5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l,6-dimethylpyridin-2(lH)-one (33); 1- (cyclopropylmethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin- 2(1 H)-one (34); 1 ,3 -diethy 1-5 -(3-isopropy 1-5 -(piperidin-4-y 1)- 1 H-indol-2-y l)-6- methylpyridin-2(lH)-one (35); l-isobutyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-3-methylpyridin-2(lH)-one (36); methyl 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-
2- yl)-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate (37); l-(3-hydroxypropyl)-5-(3- isopropy l-5-(piperidin-4-y 1)- 1 H-indol-2-y l)-3-methy lpyridin-2(l H)-one (38); 5 -(3 - isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-(2-methoxyethyl)-3-methylpyridin-2(lH)- one (39); l-(2,2-difluoroethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3- methylpyridin-2(lH)-one (40); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l- methyl-3-(trifluoromethyl)pyridin-2(lH)-one (41); 5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-3-methyl-l-(tetrahydrofuran-3-yl)pyridin-2(lH)-one (42); l-(2-hydroxy-2- methylpropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)- one (43); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methyl-l-phenylpyridin- 2(lH)-one (44); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-methyl-l-(2,2,2- trifluoroethyl)pyridin-2(lH)-one (45); l-benzyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-3-methylpyridin-2(lH)-one (46); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol- 2-yl)-l-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (47); l-(2-hydroxy-2- methylpropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)pyridin-2(lH)-one (48); 2- (5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2-oxopyridin-l(2H)-yl)acetamide (49); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (50); 5 -(3 -isopropy l-5-(piperidin-4-y 1)- 1 H-indol-2-y 1)- 1 -methy 1-3 -(prop- 1 -en-2- yl)pyridin-2(lH)-one (51); (E)-3-(2-cyclopropylvinyl)-5-(3-isopropyl-5-(piperidin-4-yl)- lH-indol-2-yl)-l-methylpyridin-2(lH)-one (52); 5-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-l-methyl-3-phenylpyridin-2(lH)-one (53); 5-(3-isopropyl-5-(piperidin-4-yl)- lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (54); 5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(p-tolyl)pyridin-2(lH)-one (55); 3-(5-(3- isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridin-3- yl)benzonitrile (56); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2'-methoxy-l- methyl-[3,3'-bipyridin]-2(lH)-one (57); 3-(5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)benzamide (58); 3-(5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-N- methylbenzamide (59); N-(3-(5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl- 2-oxo-l, 2-dihydropyridin-3-yl)phenyl)acetamide (60); 3-(3,3-dimethylbutyl)-5-(3- isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (61); 3-(2- cyclopropylethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin- 2(lH)-one (62); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-N,N,l-trimethyl-2-oxo- l,2-dihydropyridine-3-carboxamide (63); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l-methyl-2-oxo-N-propyl-l,2-dihydropyridine-3-carboxamide (64); 5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethyl-[3,3'-bipyridin]-2(lH)-one (65); 3- isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one
(66) ; 3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one
(67) ; l,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)pyridin-2(lH)-one (68); -(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrrolidine-l-carbonyl) pyridin-2(lH)-one (69); 3-(hydroxymethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2- yl)-l-methylpyridin-2(lH)-one (70); 2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (71); 5-(3- isopropyl-5-(l-((l-methyl-lH-l,2,4-triazol-3-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)- l,3-dimethylpyridin-2(lH)-one (72); 5-(5-(l-(3-hydroxy-3-methylbutyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,3,4-trimethylpyridin-2(lH)-one (73); 5-(5-(l-(3-hydroxy-3- methylbut l)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,6 rimethylpyridin-2(lH)-one (74); 5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin- 2(lH)-one (75); 3-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH- indol-5-yl)piperidin-l-yl)propanenitrile (76); 5-(3-isopropyl-5-(l-(4-(trifluoromethoxy) benzyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (77); 5-(5-(l-(5- (difluoromethoxy)-2-fluorobenzyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (78); 5-(3-isopropyl-5-(l-(4,4,4-trifluorobutyl)piperidin-4-yl)- 1 H-indol-2-y 1)- 1 ,3 -dimethy lpyridin-2(l H)-one (79); 5 -(5-( 1 -(5 -chloro-2- fluorobenzyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (80); 5-(5-(l-(l,l-dioxidotetrahydrothiophen-3-yl)piperidin-4-yl)-3-isopropyl-lH-indol- 2-yl)-l,3-dimethylpyridin-2(lH)-one (81); 3-(4-(2-(l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)propanamide (82); 5-(5- (l-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (83); l-(2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)ethyl)pyrrolidine-2,5-dione (84); 5-(5-(l-(3- hydroxypropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)- one (85); 5-(5-(l-isopentylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (86); 5-(5-(l-cyclohexylpiperidin-4-yl)-3-isopropyl-lH-indol-
2- yl)-l,3-dimethylpyridin-2(lH)-one (87); 5-(3-isopropyl-5-(l-(4,4,4-trifluoro-3- (trifluoromethyl)butyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (88); 5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-methyl-3- phenylpyridin-2(lH)-one (89); 5-(5-(l-isopentylpiperidin-4-yl)-3-isopropyl-lH-indol-2- yl)-l-methyl-3-phenylpyridin-2(lH)-one (90); 3-chloro-5-(5-(l-isopentylpiperidin-4-yl)-
3- isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (91); 3-chloro-5-(3-isopropyl- 5-(l-(oxetan-3-ylmethyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (92); 3-chloro-5-(3-isopropyl-5-(l-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)- lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (93); 5-(3-isopropyl-5-(l-(oxetan-3- ylmethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (94); 3-chloro-5-(3-isopropyl-5-(l-(2-methoxyethyl)piperidin-4-yl)-lH-indol-2-yl)-l,4- dimethylpyridin-2(lH)-one (95); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)acetonitrile (96); 3-chloro- 5-(5-(l-cyclopentylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (97); 3-chloro-5-(3-isopropyl-5-(l-(2-(2-(2-methoxyethoxy)ethoxy)ethyl) piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (98); 3-chloro-5-(3- isopropyl-5-(l-(3-methoxypropyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (99); 5-(3-isopropyl-5-(l-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)- lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (100); 3-chloro-5-(3- isopropyl-5-(l-(2-(2-methoxyethoxy)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l,4- dimethylpyridin-2(lH)-one (101); 3-chloro-5-(3-isopropyl-5-(l-(3,3,3-trifluoropropyl) piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (102); 5-(3-isopropyl-5-(l- (2-methoxyethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin- 2(lH)-one (103); 5-(3-isopropyl-5-(l-(4,4,4-trifluorobutyl)piperidin-4-yl)-lH-indol-2-yl)- l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (104); 3-chloro-5-(3-isopropyl-5-(l- (4,4,4-trifluorobuty l)piperidin-4-y 1)- 1 H-indol-2-y 1)- 1 ,4-dimethy lpyridin-2( 1 H)-one (105); 3-chloro-5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (106); 3-chloro-5-(3-isopropyl-5-(l-(2-(methylsulfonyl)ethyl) piperidin-4-yl)- lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (107); 5-(3-isopropyl-5-(l-(2- (methylsulfonyl)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl) pyridin-2(lH)-one (108); 5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-(2- methoxyethyl)-3-methylpyridin-2(lH)-one (109); l-isobutyl-5-(3-isopropyl-5-(l-(4,4,4- trifluorobutyl)piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (110); 1-benzyl- 5-(3-isopropyl-5-(l-(4,4,4-trifluorobutyl)piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin- 2(lH)-one (111); l-isobutyl-5-(5-(l-isobutylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3- methylpyridin-2(lH)-one (112); l-benzyl-5-(5-(l-isobut lpiperidin-4-yl)-3-isopropyl-lH- indol-2-yl)-3-methylpyridin-2(lH)-one (113); 2-(4-(3-isopropyl-2-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (114); 2-(4- (2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l- yl)-N-methylacetamide (117); (S)-5-(5-(l-(2-(3-hydroxypyrrolidin-l-yl)-2- oxoethyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (119); (R)-5-(5-(l-(2-(3-hydroxypyrrolidin-l-yl)-2-oxoethyl) piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (120); 5-(3-isopropyl-5-(l-(2-oxo-2-(3- oxopyrazolidin-l-yl)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (121); 5-(3 -isopropy l-5-( 1 -(2-oxo-2-(py rrolidin- 1 -y l)ethyl) piperidin-4-y 1)- lH-indol-2- yl)-l,3-dimethylpyridin-2(lH)-one (122); (R)-5-(3-isopropyl-5-(l-(2-oxopyrrolidin-3- yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (123); 2-(4-(2-(l,5- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl) piperidin-l-yl)-N- (2-hydroxy-2-methylpropyl)acetamide (124); (R)-2-(4-(2-(l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-(2- hydroxypropyl)acetamide (125); (S)-2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-(2-hydroxypropyl)acetamide (126); 5-(3- isopropyl-5-(l-(l-methyl-2-oxopyrrolidin-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (127); 2-(4-(3-isopropyl-2-(5-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (128); 2-(4- (3-isopropyl-2-(5-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl) piperidin-l-yl)-N-methylacetamide (129); 2-(4-(2-(l-ethyl-5-methyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (132); 2-(4-(2-(l-ethyl-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5- yl)piperidin-l-yl)-N,N-dimethylacetamide (133); 2-(4-(3 -isopropy l-2-( 1,4,5 -trimethy 1-6- oxo-1, 6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (134); 2-(4-(3-isopropyl-2-(l,4,5-trimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5- yl)piperidin-l-yl)-N-methylacetamide (135); 2-(4-(2-(l-ethyl-4,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (136); 2-(4-(2-(l-ethyl-4,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH- indol-5-yl)piperidin-l-yl)-N-methylacetamide (137); 2-(4-(3-isopropyl-2-(l,2,5- trimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N- dimethylacetamide (138); 2-(4-(3-isopropyl-2-(l,2,5-trimethyl-6-oxo-l,6-dihydropyridin- 3-yl)-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (139); 2-(4-(3-isopropyl-2-(5- methoxy-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N- methylacetamide (140); 2-(4-(3-isopropyl-2-(5-methoxy-l,4-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (141); 2-(4- (3-isopropyl-2-(5-methoxy-l,2-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5- yl)piperidin-l-yl)-N-methylacetamide (142); 2-(4-(3-isopropyl-2-(5-methoxy-l,2- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N- dimethylacetamide (143); 2-(4-(2-(5-cyano-l,2-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (144); 2-(4-(2-(5-cyano- l,2-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)- N,N-dimethylacetamide (145); 2-(4-(2-(5-cyano-l,4-dimethyl-6-oxo-l,6-dihydropyridin- 3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (146); 2-(4-(2-(5- cyano-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin- l-yl)-N,N-dimethylacetamide (147); 2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-2-methylpropanoic acid (148); 5-(3- isopropyl-5-(l-(5-methyl-2-oxotetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (149); 2-(4-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)acetamide (150); 2-(4-(2-(l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-2-methylpropanamide (151); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH- indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (152); 2-(4-(2-(5-chloro-l,4-dimethyl- 6-oxo-l, 6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N- methylacetamide (153); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-2-methylpropanamide (154); 2-(4-(2-(5-chloro- l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)- N-ethylacetamide (155); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-
3- isopropyl-lH-indol-5-yl)piperidin-l-yl)propanamide (156); 2-(4-(2-(5-chloro-l,4- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-ethyl-lH-indol-5-yl) piperidin-l-yl)-N,N- dimethylacetamide (157); 2-(4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-
4- fluoro-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (158); 2-(4- (3-isopropyl-2-(l-(2-methoxyethyl)-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-
5- yl)piperidin-l-yl)-N,N-dimethylacetamide (159); 2-(4-(3-isopropyl-2-(l-(2- methoxyethyl)-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l-yl)- N-methylacetamide (160); 2-(4-(2-(l-isobutyl-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (161); 2-(4-(2-(l-benzyl-5- methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N- methylacetamide (162); 2-(4-(2-(l-isobutyl-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (163); 2-(4-(2-(l- benzyl-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l- yl)-N,N-dimethylacetamide (164); 2-(4-(3 -isopropyl-2-(5-methyl-6-oxo-l -(2,2,2- trifluoroethy 1)- 1 ,6-dihy dropy ridin-3 -y 1)- lH-indol-5 -y l)piperidin- 1 -y 1)-N,N- dimethylacetamide (165); 2-(4-(2-(l-(2,2-difluoroethyl)-5-methyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (166); 2-(4-(2-(l-(2 -hydroxy ethyl)-5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl- lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (167); 2-(4-(2-(5-ethyl-l-methyl- 6-oxo-l, 6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N,N- dimethylacetamide (168); 2-(4-(3-isopropyl-2-(l-methyl-2-oxo-l,2-dihydro-[3,3'- bipyridin]-5-yl)-lH-indol-5-yl)piperidin-l-yl)-N,N-dimethylacetamide (169); 2-(4-(3- isopropyl-2-(l-methyl-6-oxo-5-phenyl-l,6-dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-
1- yl)-N,N-dimethylacetamide (170); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (171); 5-(3-isopropyl-5-(l-(2- (methylamino)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (172); 5- (3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(piperidin-l-yl) pyridin-2(lH)-one (173); 5-(5-(l-(l-acetylazetidin-3-yl)piperidin-4-yl)-3-isopropyl-lH- indol-2-y l)-3-chloro- 1 ,4-dimethylpyridin-2( 1 H)-one (174); 5 -(3 -isopropyl-5 -( 1 -(oxetan- 3-yl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (175); 5-(3-isopropyl-5- (l-(2-(methylamino)ethyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (176); 5-(3-isopropyl-5-(l-(tetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l- methylpyridin-2(lH)-one (177); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl) piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (178); 5-(3-isopropyl-5-(l- (oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (179); 5-(3- isopropyl-5-(l-(tetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin- 2(lH)-one (180); 5-(3-isopropyl-5-(l-methylpiperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (181); 5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-
2- yl)-l,3-dimethylpyridin-2(lH)-one (182); 5-(3-isopropyl-5-(l-((l-methyl-lH-pyrazol-
3- yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (195); 5-(3- isopropyl-5-(l-((l-methyl-lH-pyrazol-4-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (196); 5-(3-isopropyl-5-(l-((l-methyl-lH-pyrazol-5-yl) methyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (197); 5-(3- isopropyl-5-(l-((l-methyl-lH-l,2,4-triazol-5-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)- l,3-dimethylpyridin-2(lH)-one (198); 5-(5-(l-(4,4-difluorocyclohexyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (199); 5-(5-(l-((4H-pyrazol-3- yl)methyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (200); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3- methoxy-l-methylpyridin-2(lH)-one (201); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4- yl)-lH-indol-2-yl)-3-methoxy-l-methylpyridin-2(lH)-one (202); l-ethyl-5-(3-isopropyl- 5-(l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (204); 5-(3- isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3,4- trimethylpyridin-2(lH)-one (206); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-l,3,4-trimethylpyridin-2(lH)-one (207); l-ethyl-5-(3-isopropyl-5-(l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3,4-dimethylpyridin-2(lH)-one (208); l-ethyl-5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-3,4- dimethylpyridin-2(lH)-one (209); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl) piperidin-4-yl)-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)-one (210); 5-(3-isopropyl-5- (l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)-one (211); 5- (3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,3,4-trimethylpyridin-2(lH)- one (212); l-ethyl-5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-3,4- dimethylpyridin-2(lH)-one (213); 5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol- 2-yl)-l,3,6-trimethylpyridin-2(lH)-one (214); 5-(3-isopropyl-5-(l-(oxetan-3-yl) piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l,4-dimethylpyridin-2(lH)-one (215); 5-(3- isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l,4- dimethylpyridin-2(lH)-one (216); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-3-methoxy-l,6-dimethylpyridin-2(lH)-one (217); 5-(3-isopropyl-5-(l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3-methoxy-l,6- dimethylpyridin-2(lH)-one (218); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH- indol-2-yl)-l,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (219); 5-(3-isopropyl- 5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l,6-dimethyl-2-oxo-l,2- dihydropyridine-3-carbonitrile (220); 5-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)- lH-indol-2-yl)-l,4-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (221); 5-(3- isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethyl-2- oxo-1, 2-dihydropyridine-3-carbonitrile (222); 5-(5-(l-(cyclopropylmethyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (223); 5-(3-isopropyl-5- (l-propylpiperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (224); 5-(3- isopropyl-5-(l-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (225); 3-chloro-5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4- yl)piperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (226); 3-chloro-5-(3- isopropyl-5-(l-((l-isopropyl-lH-pyrazol-4-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l- methylpyridin-2(lH)-one (227); 5-(3-isopropyl-5-(l-((l-propyl-lH-pyrazol-4-yl)methyl) piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (228); N-(4-(4-(2-(l,5- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl) cyclohexyl)acetamide (229); 5-(3-isopropyl-5-(l-(4-(trifluoromethyl)cyclohexyl) piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (230); 5-(3-isopropyl-5-(l- (4-(trifluoromethyl)cyclohexyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin- 2(lH)-one (231); 5-(5-(l-((l,3-dimethyl-lH-pyrazol-4-yl)methyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (232); 5-(3-isopropyl-5-(l-(4- isopropylcyclohexyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (233); 5-(3-isopropyl-5-(l-(4-isopropylcyclohexyl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpy ridin-2(l H)-one (234); 5 -(3 -isopropy 1-5 -( 1 -isopropy lpiperidin-4-y 1)- 1 H-indol-
2- yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (235); 5-(5-(l-(2-hydroxyethyl)piperidin-4-yl)-
3- isopropyl-lH-indol-2-yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (236); 5-(3-isopropyl-5- (l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,4-dimethyl-[3,3'-bipyridin]-2(lH)-one (237); 3-chloro-5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,4- dimethylpyridin-2(lH)-one (238); 3-chloro-5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4- y l)piperidin-4-y 1)- 1 H-indol-2-y 1)- 1 ,4-dimethy lpy ridin-2(l H)-one (241 ); 3 -chloro-5 -(3 - isopropyl-5-(l-methylpiperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (240); 5-(5-(l-acetylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-chloro-l,4- dimethylpy ridin-2(l H)-one (241 ); 3 -chloro-5 -(3 -isopropy 1-5 -( 1 -propy lpiperidin-4-y 1)- 1 H- indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (242); 3-chloro-5-(5-(l-(l,5-dihydroxypentan- 3-yl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (243); 5- (3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5- yl)pyridin-2(lH)-one (244); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l- methyl-[3,3'-bipyridin]-2(lH)-one (245); 5-(3-isopropyl-5-(l-methylpiperidin-4-yl)-lH- indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (246); 5-(3-isopropyl-5-(l- methylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (247); 3- chloro-5-(3-isopropy 1-5 -( 1 -(oxetan-3 -y l)piperidin-4-y 1)- 1 H-indol-2-y 1)- 1,4- dimethylpy ridin-2(l H)-one (248); 5 -(3 -isopropy 1-5 -( 1 -propy lpiperidin-4-y 1)- 1 H-indol-2- yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (249); 3-chloro-5-(3-isopropyl-5-(l- ((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)- one (250); 5-(5-(l-butylpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-chloro-l,4- dimethylpyridin-2(lH)-one (251); 3-chloro-5-(3-isopropyl-5-(l-((tetrahydrofuran-3- yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (252); 3-chloro- 5 -(5 -( 1 -(2,3-dihy droxypropy l)piperidin-4-y l)-3-isopropy 1- 1 H-indol-2-y 1)- 1 ,4- dimethylpyridin-2(lH)-one (253); 3-chloro-5-(3-isopropyl-5-(l-((tetrahydrofuran-3- yl)methyl)piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (254-255); 5-(5- (l-isobut lpiperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5- yl)pyridin-2(lH)-one (256); 5-(3-isopropyl-5-(l-((tetrahydrofuran-3-yl)methyl)piperidin- 4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (257); 5-(4-fluoro-3- isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin- 2(lH)-one (258); 5-(4-fluoro-3-isopropyl-5-(l-((tetrahydrofuran-3-yl)methyl)piperidin-4- yl)-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (259); l-ethyl-5-(3- isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-3-(pyrimidin-5-yl)pyridin-2(lH)-one (260); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-l- (2-methoxyethyl)-3-methylpyridin-2(lH)-one (261); l-isobutyl-5-(3-isopropyl-5-(l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (262); l-benzyl-5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol- 2-yl)-3-methylpyridin-2(lH)-one (263); l-(2-hydroxyethyl)-5-(3-isopropyl-5-(l- methylpiperidin-4-yl)-lH-indol-2-yl)-3-methylpyridin-2(lH)-one (264); 5-(3-isopropyl-5- (l-methylpiperidin-4-yl)-lH-indol-2-yl)-3-methyl-l-(2,2,2-trifluoroethyl)pyridin-2(lH)- one (265); l-(2,2-difluoroethyl)-5-(3-isopropyl-5-(l-methylpiperidin-4-yl)-lH-indol-2- yl)-3-methylpyridin-2(lH)-one (266); 5-(5-(l-(4-(2-hydroxypropan-2- yl)cyclohexyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (267-268); 5-(3-isopropyl-5-(l-(l-(l-methyl-lH-pyrazol-4-yl)ethyl)piperidin-4-yl)-lH- indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (269); 5-(5-(l-(4-(2-hydroxypropan-2- yl)cyclohexyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (270); 5-(5-(l-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (271); 5-(5-(l-(l-aminocyclopropanecarbonyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (272); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,6-dimethyl-2-oxo-l,2- dihydropyridine-3-carbonitrile (273); 5-(5-(l -(dimethylglycyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,4-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (274); 5- (5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-methoxy-l,6- dimethylpyridin-2(lH)-one (275); 5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-3-methoxy-l,4-dimethylpyridin-2(lH)-one (276); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-(methoxymethyl)-l- methylpyridin-2(lH)-one (277); 3-chloro-5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (278); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,6 rimethylpyridin-2(lH)- one (279); 5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,4- trimethylpyridin-2(lH)-one (280); 5-(5-(l-(dimethylglycyl) piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-l-ethyl-3,4-dimethylpyridin-2(lH)-one (281); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-ethyl-3-methylpyridin- 2(lH)-one (282); l-benzyl-5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol- 2-yl)-3-methylpyridin-2(lH)-one (284); 5-(5-(l-(dimethylglycyl) piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l-isobutyl-3-methylpyridin-2(lH)-one (285); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-methoxy-l-methylpyridin- 2(lH)-one (286); 5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l- (2-methoxyethyl)-3-methylpyridin-2(lH)-one (287); 5-(5-(l-((2R,4S)-4- hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (288); 5-(5-(l-((2S,4R)-4-hydroxy-l-methylpyrrolidine-2- carbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (289); 5-(5-(l-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-lH- indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (290); 5-(5-(l-((2S,3S)-3-hydroxypyrrolidine- 2-carbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (291); 5-(5-(l-((2R,4S)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-lH- indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (292); 5-(5-(l-((2S,4R)-4-hydroxypyrrolidine- 2-carbonyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (293); 5-(5-(l-(2-amino-2-methylpropanoyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)- l,3-dimethylpyridin-2(lH)-one (296); 5-(3-isopropyl-5-(l-(methyl-L-alanyl)piperidin-4- yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (297); 5-(3-isopropyl-5-(l-(2-methyl- 2-(methylamino)propanoyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)- one (298); 5-(3-isopropyl-5-(l-(methyl-D-alanyl)piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (299); 5-(3-isopropyl-5-(l-(2-(2-oxopyrrolidin-l- yl)acetyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (300); 5-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (301); 3-chloro-5-(3-isopropyl-5-(l-(2,2,2-trifluoroacetyl) piperidin-4-yl)-lH-indol-2-yl)- l,4-dimethylpyridin-2(lH)-one (302); 5-(5-(l-(3-hydroxy-3-methylbutanoyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (303); 5-(5-(l-(3-hydroxy- 2,2-dimethylpropanoyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin- 2(lH)-one (304); (S)-5-(5-(l-(3-hydroxybutanoyl) piperidin-4-yl)-3-isopropyl-lH-indol- 2-yl)-l,3-dimethylpyridin-2(lH)-one (305); (R)-5-(3-isopropyl-5-(l-(2-(pyrrolidin-2- yl)acetyl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (306); (S)-l- methylpyrrolidin-3-yl 4-(2-(5-chloro-l,4-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (307); 3-chloro-5-(3-isopropyl-5-(l- ((2-(pyrrolidin-l-yl)ethyl)sulfonyl) piperidin-4-yl)-lH-indol-2-yl)-l,4-dimethylpyridin- 2(lH)-one (308); 3-chloro-5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,4-dimethylpyridin-2(lH)-one (309); 5-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (310); 5-(5-(l-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)piperidin-4-yl)-3-isopropyl- 1 H-indol-2-y 1)- 1 ,3 -dimethy lpyridin-2( 1 H)-one (313); 5 -(5 -( 1 -((3 S,4S)-4- hydroxytetrahydro-2H-pyran-3-yl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (314); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l,3,4-trimethylpyridin-2(lH)-one (315); 5-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)- one (316); 5-(5-(l-(2-hydroxy-2-methylpropyl) piperidin-4-yl)-3-isopropyl-lH-indol-2- yl)-3-methoxy-l,4-dimethylpyridin-2(lH)-one (317); 5-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3-methoxy-l,6- dimethylpyridin-2(lH)-one (318); 5-(5-(l -((4-hydroxytetrahydro-2H-pyran-4- yl)methyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3,4-trimethylpyridin-2(lH)-one (319); 5-(5-(l -((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-l,3,6-trimethylpyridin-2(lH)-one (320); 5-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,6-dimethyl-2-oxo-l,2- dihydropyridine-3-carbonitrile (321); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)- 3-isopropyl-lH-indol-2-yl)-l,4-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (322); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3- (methoxymethyl)-l-methylpyridin-2(lH)-one (323); 5-(5-(l-(2-hydroxy-3-methylbutyl) piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (324); 5-(5-(l- (2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-l,3- dimethylpyridin-2(lH)-one (325); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3- isopropyl-lH-indol-2-yl)-l-methyl-3-(pyrimidin-5-yl)pyridin-2(lH)-one (326); 3-chloro- 5-(4-fluoro-5-(l-(2 -hydroxy -2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)- l,4-dimethylpyridin-2(lH)-one (327); 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4- yl)-3-isopropyl-lH-indol-2-yl)-l-isobutyl-3-methylpyridin-2(lH)-one (328); l-benzyl-5- (5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-3- methylpyridin-2(lH)-one (329); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2- yl)-l-methyl-6'-morpholino-[3,3'-bipyridin]-2(lH)-one (330); 5-(3-isopropyl-5-(l- propylpiperidin-4-yl)-lH-indol-2-yl)-3-(2-methoxypyrimidin-5-yl)-l-methylpyridin- 2(lH)-one (331); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l,5'-dimethyl- [3,3'-bipyridin]-2(lH)-one (332); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2- yl)-l,4-dimethyl-3-(l-methyl-lH-pyrazol-4-yl)pyridin-2(lH)-one (333); 5-(3-isopropyl- 5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(l-methyl-lH-pyrazol-4-yl) pyridin-2(lH)-one (334); N-(5'-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-r- methyl-2'-oxo- ,2'-dihydro-[3,3'-bipyridin]-6-yl)acetamide (335); 5-(3-isopropyl-5-(l- propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,4'-bipyridin]-2(lH)-one (336); 5-(3- isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(2-methylpyrimidin-5- yl)pyridin-2(lH)-one (337); 3-(2-cyclopropylpyrimidin-5-yl)-5-(3-isopropyl-5-(l- propylpiperidin-4-yl)-lH-indol-2-yl)-l-methylpyridin-2(lH)-one (338); 5-(3-isopropyl-5- (l-propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl) pyridin-2(lH)-one (339); 5-(3-isopropyl-5-(l-propylpiperidin-4-yl)-lH-indol-2-yl)-3-(3- methoxyphenyl)-l-methylpyridin-2(lH)-one (340); 6'-fluoro-5-(3-isopropyl-5-(l- propylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,3'-bipyridin]-2(lH)-one (341); 6'- fluoro-5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l-methyl-[3,3'- bipyridin]-2(lH)-one (342); 6'-fluoro-5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH- indol-2-yl)-l,5'-dimethyl-[3,3'-bipyridin]-2(lH)-one (343); 5-(3-isopropyl-5-(l- isopropylpiperidin-4-yl)-lH-indol-2-yl)-l ,2'-dimethyl-[3,3'-bipyridin]-2(lH)-one (244); 5-(3-isopropyl-5-(l -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-3- (methoxymethyl)-l-methylpyridin-2(lH)-one (345); 5-(3-isopropyl-5-(l -(oxetan-3-yl) piperidin-4-yl)-lH-indol-2-yl)-3-(methoxymethyl)-l-methylpyridin-2(lH)-one (346); 5- (3-isopropyl-5-(l -isopropylpiperidin-4-yl)-lH-indol-2-yl)-3-(methoxymethyl)-l- methylpyridin-2(lH)-one (347); 5-(3-isopropyl-5-(l -propylpiperidin-4-yl)-lH-indol-2- yl)-3-(methoxymethyl)-l-methylpyridin-2(lH)-one (348); 5-(3-isopropyl-5-(l-(2- methoxyethyl)piperidin-4-yl)-lH-indol-2-yl)-l,6'-dimethyl-[3,3'-bipyridin]-2(lH)-one (349); 5-(3-isopropyl-5-(l -(2-methoxyethyl)piperidin-4-yl)-lH-indol-2-yl)-l -methyl-3- (l-methyl-lH-pyrazol-4-yl)pyridin-2(lH)-one (350); 2-(4-(3-isopropyl-2-(5- (methoxy methyl)- 1 -methy 1-6-oxo- 1 ,6-dihy dropy ridin-3-y 1)- lH-indol-5 -y l)piperidin- 1 - yl)-N,N-dimethylacetamide (351); 2-(4-(3-isopropyl-2-(l -methyl-6-oxo-5-vinyl-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)piperidin-l -yl)-N,N-dimethylacetamide (352); and 5- (3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-3-(methoxymethyl)-l -methylpyridin- 2(lH)-one (353).
7. The compound according to claim 1 or a salt thereof, wherein said compound is selected from 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l -methylpyrazin-2(lH)- one (4); 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2-methylpyridazin-3(2H)-one (5); 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2,5-dimethylpyridazin-3(2H)-one
(10) ; 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one
(11) ; 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l ,3-dimethylpyrazin-2(lH)-one
(12) ; 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)- one (17); 2-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-4-methylpyridazin- 3(2H)-one (18); 5-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-l,3- dimethylpyrimidine-2,4(lH,3H)-dione (21); 2-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-lH- indol-2-yl)-4,5-dimethylpyridazin-3(2H)-one (27); 2-(4-(2-(4,6-dimethyl-5-oxo-4,5- dihydropyrazin-2-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l -yl)-N,N-dimethylacetamide (115); 2-(4-(2-(l,5-dimethyl-6-oxo-l ,6-dihydropyridazin-3-yl)-3-isopropyl-lH-indol-5- yl)piperidin-l -yl)-N,N-dimethylacetamide (1 16); 2-(4-(2-(l ,5-dimethyl-6-oxo-l ,6- dihydropyridazin-3-yl)-3-isopropyl-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (118); 2-(4-(3-isopropyl-2-(l,4,5-trimethyl-6-oxo-l,6-dihydropyridazin-3-yl)-lH-indol-5- yl)piperidin-l-yl)-N,N-dimethylacetamide (130); 2-(4-(3-isopropyl-2-( 1,4,5 -trimethy 1-6- oxo-1, 6-dihydropyridazin-3-yl)-lH-indol-5-yl)piperidin-l-yl)-N-methylacetamide (131); 5 -(3 -isopropy 1-5 -( 1 -methy lpiperidin-4-y 1)- lH-indol-2-y 1)- 1 ,3-dimethy lpy razin-2( 1 H)-one (183); 5-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin- 2(lH)-one (184); 5-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH- indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (185); 5-(3-isopropyl-5-(l-(oxetan-3-yl) piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (186); 5-(3-isopropyl-5- (l-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH)- one (187); 6-(3-isopropyl-5-(l-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl)-lH-indol-2-yl)- 2,4-dimethylpyridazin-3(2H)-one (188); 6-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)- lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one (189); 5-(3-isopropyl-5-(l- (tetrahydrofuran-3-yl)piperidin-4-yl)-lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (190); 6-(3-isopropyl-5-(l-methylpiperidin-4-yl)-lH-indol-2-yl)-2,4-dimethylpyridazin- 3(2H)-one (191); 6-(3-isopropyl-5-(l-isopropylpiperidin-4-yl)-lH-indol-2-yl)-2,4- dimethylpyridazin-3(2H)-one (192); 6-(3-isopropyl-5-(l-(tetrahydrofuran-3-yl)piperidin- 4-yl)-lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one (193); 6-(3-isopropyl-5-(l- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)- one (194); 6-(3-isopropyl-5-(l-(oxetan-3-yl)piperidin-4-yl)-lH-indol-2-yl)-2,4,5- trimethylpyridazin-3(2H)-one (203); 6-(3-isopropyl-5-(l -(tetrahydro-2H-pyran-4-yl) piperidin-4-yl)-lH-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one (205); 6-(5-(l- (dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-2,4,5-trimethylpyridazin- 3(2H)-one (283); 6-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-2,4- dimethylpyridazin-3(2H)-one (294); 5-(5-(l-(dimethylglycyl)piperidin-4-yl)-3-isopropyl- lH-indol-2-yl)-l,3-dimethylpyrazin-2(lH)-one (295); 6-(5-(l-(2-hydroxy-2- methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol-2-yl)-2,4-dimethylpyridazin-3(2H)- one (311); and 5-(5-(l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-lH-indol- 2-yl)-l,3-dimethylpyrazin-2(lH)-one (312).
8. A pharmaceutical composition comprising a compound according to any one of claims 1-7 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1-7 or a pharmaceutically- acceptable salt thereof, in the manufacture of a medicament for the treatment of autoimmune disease or chronic inflammatory disease.
10. A compound according to any one of claims 1-7 or a pharmaceutically-acceptable salt thereof, or a pharmaceutically-acceptable salt thereof, for use in therapy in treating autoimmune disease or chronic inflammatory disease.
1 1. The compound according to claim 10 or a pharmaceutically-acceptable salt thereof, wherein said autoimmune disease or chronic inflammatory disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjogren's syndrome.
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